chr11-103184969-A-T

Position:

chr11-103184969-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The ENST00000375735.7(DYNC2H1):c.6551A>T(p.Asp2184Val) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,611,332 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00093 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

DYNC2H1
ENST00000375735.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 5.87

Variant links:

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in ENST00000375735.7

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0069859624).

BP6

Variant 11-103184969-A-T is Benign according to our data. Variant chr11-103184969-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281769.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.6551A>T	p.Asp2184Val	missense_variant	41/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.6551A>T	p.Asp2184Val	missense_variant	41/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.6551A>T	p.Asp2184Val	missense_variant	41/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.6551A>T	p.Asp2184Val	missense_variant	41/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+50550A>T		intron_variant		1		ENSP00000334021		Q8NCM8-3
DYNC2H1	ENST00000649323.1 linkuse as main transcript	c.*4096A>T		3_prime_UTR_variant, NMD_transcript_variant	39/51			ENSP00000497581

Frequencies

GnomAD3 genomes

AF:

0.000915

AC:

139

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000189

AC:

AN:

248402

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134764

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000678

AC:

AN:

1459298

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

725916

show subpopulations

Gnomad4 AFR exome

AF:

0.00255

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000927

AC:

141

AN:

152034

Hom.:

Cov.:

AF XY:

0.000915

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.000865

ESP6500AA

AF:

0.00400

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000265

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 17, 2020	The sequence change, c.6551A>T, in exon 41 that results in an amino acid change, p.Asp2184Val. This sequence change has been previously reported in product of conception samples of a couple with recurrent miscarriages in the compound heterozygous state along with other missense change, p.Tyr2016Cys, in the same gene (PMID: 26826164). No functional studies were performed. This sequence change has been described in the gnomAD database with a low population frequency of 0.32% in the African subpopulation (dbSNP rs201967064). The p.Asp2184Val change affects a moderately conserved amino acid residue located in a domain of the DYNC2H1 protein that is known to be functional. The p.Asp2184Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp2184Val change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2024	Variant summary: DYNC2H1 c.6551A>T (p.Asp2184Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a neutral effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248402 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.6551A>T has been reported in the literature in one individual affected with recurrent early pregnancy loss. These report(s) do not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26826164). ClinVar contains an entry for this variant (Variation ID: 281769). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	Identified in the the heterozygous state in an indvidual whose partner had recurrent miscarriage and was heterozygous for another variant in the DYNC2H1 gene (Qiao et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26826164) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2018	The DYNC2H1 c.6551A>T; p.Asp2184Val variant (rs201967064, ClinVar variant ID 281769) was found in the compound heterozygous state along with another DYNC2H1 variant (p.Tyr2016Cys) in two miscarriages from a family with recurrant pregnancy loss (Qiao 2106). This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.3% (identified on 75 out of 23,960 chromosomes). The aspartic acid at position 2184 is moderately conserved, considering 28 species, and computational analyses of the effects of the p.Asp2184Val variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Asp2184Val variant cannot be determined with certainty. -

DYNC2H1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Jeune thoracic dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.20

T;T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.040

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

.;T;.;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.0070

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.7

D;.;.;D

REVEL

Benign

0.13

Sift

Benign

0.080

T;.;.;T

Sift4G

Benign

0.18

T;.;.;T

Polyphen

0.010

B;B;B;B

Vest4

0.58

MVP

0.41

MPC

0.098

ClinPred

0.049

GERP RS

3.7

Varity_R

0.21

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over