11-103154567-G-T

Position:

chr11-103154567-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001377.3(DYNC2H1):c.3419G>T(p.Gly1140Val) variant causes a missense change. The variant allele was found at a frequency of 0.000575 in 1,602,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.31

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03889659).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.3419G>T	p.Gly1140Val	missense_variant	23/90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.3419G>T	p.Gly1140Val	missense_variant	23/89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 link	c.3419G>T	p.Gly1140Val	missense_variant	23/90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.3419G>T	p.Gly1140Val	missense_variant	23/89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000677

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000394

AC:

AN:

233592

Hom.:

AF XY:

0.000459

AC XY:

AN XY:

126270

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000494

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000335

Gnomad NFE exome

AF:

0.000626

Gnomad OTH exome

AF:

0.000522

GnomAD4 exome

AF:

0.000592

AC:

858

AN:

1450522

Hom.:

Cov.:

AF XY:

0.000593

AC XY:

427

AN XY:

720442

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000603

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.000715

Gnomad4 OTH exome

AF:

0.000467

GnomAD4 genome

AF:

0.000421

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000677

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000642

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000492

AC:

ExAC

AF:

0.000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	The DYNC2H1 c.3419G>T; p.Gly1140Val variant, to our knowledge, is not described in the medical literature but is reported as a variant of uncertain clinical significance in ClinVar (Variation ID: 302025). It is observed in the general population at an overall frequency of 0.04% (107/264972 alleles) in the Genome Aggregation Database. The glycine at codon 1140 is highly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Short rib-polydactyly syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Jeune thoracic dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

.;D;D;.;.

Eigen

Benign

0.066

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;D;.;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.039

T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.9

.;M;M;M;M

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

.;D;.;.;D

REVEL

Benign

0.26

Sift

Uncertain

0.029

.;D;.;.;D

Sift4G

Uncertain

0.039

.;D;.;.;D

Polyphen

0.30, 0.26

.;B;B;B;B

Vest4

0.66, 0.65

MVP

0.53

MPC

0.14

ClinPred

0.15

GERP RS

2.5

Varity_R

0.54

gMVP

0.52

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