11-103187397-C-T

Position:

• chr11-103187397-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001377.3(DYNC2H1):​c.6951C>T​(p.His2317His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,612,840 control chromosomes in the GnomAD database, including 310,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31003 hom., cov: 31)
  • Exomes 𝑓: 0.62 (279605 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.71

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-103187397-C-T is Benign according to our data. Variant chr11-103187397-C-T is described in ClinVar as [Benign]. Clinvar id is 93529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103187397-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.6951C>T	p.His2317His	synonymous_variant	43/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6951C>T	p.His2317His	synonymous_variant	43/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6951C>T	p.His2317His	synonymous_variant	43/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.6951C>T	p.His2317His	synonymous_variant	43/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96667 AN: 151742 Hom.: 30974 Cov.: 31

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.627

GnomAD3 exomes AF: 0.637 AC: 158480 AN: 248682 Hom.: 51185 AF XY: 0.630 AC XY: 84962 AN XY: 134898

Gnomad AFR exome AF: 0.663

Gnomad AMR exome AF: 0.766

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.542

Gnomad SAS exome AF: 0.558

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.617 AC: 901343 AN: 1460980 Hom.: 279605 Cov.: 63 AF XY: 0.614 AC XY: 446597 AN XY: 726778

Gnomad4 AFR exome AF: 0.672

Gnomad4 AMR exome AF: 0.756

Gnomad4 ASJ exome AF: 0.672

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.635

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.621

GnomAD4 genome AF: 0.637 AC: 96753 AN: 151860 Hom.: 31003 Cov.: 31 AF XY: 0.636 AC XY: 47167 AN XY: 74214

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.705

Gnomad4 ASJ AF: 0.676

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.629

Alfa AF: 0.633 Hom.: 14144

Bravo AF: 0.647

Asia WGS AF: 0.559 AC: 1944 AN: 3476

EpiCase AF: 0.631

EpiControl AF: 0.635

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Short rib-polydactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.4
DANN	Benign	0.40

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

Other links and lift over

dbSNP: rs586592; hg19: chr11-103058126; COSMIC: COSV62088517;