11-103456351-A-C

Position:

chr11-103456351-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000375735.7(DYNC2H1):c.12643A>C(p.Ile4215Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,595,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I4215I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

DYNC2H1
ENST00000375735.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.47

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010581374).

BP6

Variant 11-103456351-A-C is Benign according to our data. Variant chr11-103456351-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 291231.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.12664A>C	p.Ile4222Leu	missense_variant	88/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.12643A>C	p.Ile4215Leu	missense_variant	87/89	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.12664A>C	p.Ile4222Leu	missense_variant	88/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.12643A>C	p.Ile4215Leu	missense_variant	87/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000211

AC:

AN:

217750

Hom.:

AF XY:

0.000154

AC XY:

AN XY:

116942

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.0000639

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:

0.000182

GnomAD4 exome

AF:

0.0000797

AC:

115

AN:

1443070

Hom.:

Cov.:

AF XY:

0.0000684

AC XY:

AN XY:

715856

show subpopulations

Gnomad4 AFR exome

AF:

0.00274

Gnomad4 AMR exome

AF:

0.0000710

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:

0.00000726

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152296

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00322

Gnomad4 AMR

AF:

0.000131

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:

0.000121

Hom.:

Bravo

AF:

0.000963

ESP6500AA

AF:

0.00326

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000282

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.12664A>C (p.I4222L) alteration is located in exon 88 (coding exon 88) of the DYNC2H1 gene. This alteration results from a A to C substitution at nucleotide position 12664, causing the isoleucine (I) at amino acid position 4222 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Asphyxiating thoracic dystrophy 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 24, 2022

- -

DYNC2H1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

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 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.089

T;.;T;.;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

.;T;T;.;T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.011

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;L;.;.;.

MutationTaster

Benign

0.96

D;D;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

N;N;.;.;N;N

REVEL

Benign

0.080

Sift

Benign

0.081

T;T;.;.;T;T

Sift4G

Uncertain

0.047

D;T;.;.;D;D

Polyphen

0.013

B;D;B;B;B;.

Vest4

0.44

MVP

0.39

MPC

0.061

ClinPred

0.066

GERP RS

1.6

Varity_R

0.18

gMVP

0.38

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