11-103154736-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001377.3(DYNC2H1):c.3500A>G(p.His1167Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000213 in 1,573,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.08

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 Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008294135).

BP6

Variant 11-103154736-A-G is Benign according to our data. Variant chr11-103154736-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188353.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr11-103154736-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00113 (172/152240) while in subpopulation AFR AF= 0.00409 (170/41566). AF 95% confidence interval is 0.00359. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.3500A>G	p.His1167Arg	missense_variant	Exon 24 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.3500A>G	p.His1167Arg	missense_variant	Exon 24 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 link	c.3500A>G	p.His1167Arg	missense_variant	Exon 24 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.3500A>G	p.His1167Arg	missense_variant	Exon 24 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000339

AC:

AN:

191696

Hom.:

AF XY:

0.000314

AC XY:

AN XY:

101752

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000417

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000115

AC:

163

AN:

1421410

Hom.:

Cov.:

AF XY:

0.0000939

AC XY:

AN XY:

702858

show subpopulations

Gnomad4 AFR exome

AF:

0.00386

Gnomad4 AMR exome

AF:

0.000260

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000250

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.000356

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152240

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00409

Gnomad4 AMR

AF:

0.0000654

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:

0.000200

Hom.:

Bravo

AF:

0.00135

ESP6500AA

AF:

0.00275

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000335

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 01, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DYNC2H1-related disorder

Benign:1

Jul 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.13

.;T;T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.081

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;.;D;.;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.0083

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;L;L;L

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

.;N;.;.;N

REVEL

Benign

0.16

Sift

Benign

0.53

.;T;.;.;T

Sift4G

Benign

0.52

.;T;.;.;T

Polyphen

0.0040, 0.0030

.;B;B;B;B

Vest4

0.56, 0.56

MVP

0.64

MPC

0.073

ClinPred

0.037

GERP RS

5.6

Varity_R

0.24

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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