11-103109595-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_001080463.2(DYNC2H1):c.21C>T(p.Asp7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,613,576 control chromosomes in the GnomAD database, including 7,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (436 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6608 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.28

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=-0.44).
• BP6: Variant 11-103109595-C-T is Benign according to our data. Variant chr11-103109595-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 301995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103109595-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.21C>T	p.Asp7=	synonymous_variant	1/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.21C>T	p.Asp7=	synonymous_variant	1/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.21C>T	p.Asp7=	synonymous_variant	1/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.21C>T	p.Asp7=	synonymous_variant	1/89	1	NM_001377.3	P3

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9955 AN: 152128 Hom.: 435 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.0753

GnomAD3 exomes AF: 0.0736 AC: 18308 AN: 248748 Hom.: 882 AF XY: 0.0776 AC XY: 10475 AN XY: 134940

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.0925

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0833

GnomAD4 exome AF: 0.0892 AC: 130393 AN: 1461330 Hom.: 6608 Cov.: 31 AF XY: 0.0897 AC XY: 65213 AN XY: 726904

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.0520

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0944

Gnomad4 FIN exome AF: 0.0455

Gnomad4 NFE exome AF: 0.0967

Gnomad4 OTH exome AF: 0.0863

GnomAD4 genome AF: 0.0654 AC: 9958 AN: 152246 Hom.: 436 Cov.: 32 AF XY: 0.0636 AC XY: 4735 AN XY: 74440

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0858

Gnomad4 FIN AF: 0.0459

Gnomad4 NFE AF: 0.0951

Gnomad4 OTH AF: 0.0745

Alfa AF: 0.0903 Hom.: 870

Bravo AF: 0.0634

Asia WGS AF: 0.0280 AC: 100 AN: 3478

EpiCase AF: 0.0970

EpiControl AF: 0.102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	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 -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -

Jeune thoracic dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Asphyxiating thoracic dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	11
Dann	Benign	0.89

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

Other links and lift over

dbSNP: rs17301028; hg19: chr11-102980324;