rs77738279

chr11-103135828-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080463.2(DYNC2H1):c.2454G>A(p.Glu818=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,612,950 control chromosomes in the GnomAD database, including 1,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (107 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1671 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.130

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-103135828-G-A is Benign according to our data. Variant chr11-103135828-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 302018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103135828-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.2454G>A	p.Glu818=	synonymous_variant	17/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.2454G>A	p.Glu818=	synonymous_variant	17/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.2454G>A	p.Glu818=	synonymous_variant	17/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.2454G>A	p.Glu818=	synonymous_variant	17/89	1	NM_001377.3	P3

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5087 AN: 152094 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.0644

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0322

GnomAD3 exomes AF: 0.0412 AC: 10208 AN: 247832 Hom.: 262 AF XY: 0.0442 AC XY: 5941 AN XY: 134392

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.0204

Gnomad ASJ exome AF: 0.0336

Gnomad EAS exome AF: 0.0614

Gnomad SAS exome AF: 0.0692

Gnomad FIN exome AF: 0.0367

Gnomad NFE exome AF: 0.0430

Gnomad OTH exome AF: 0.0419

GnomAD4 exome AF: 0.0453 AC: 66183 AN: 1460738 Hom.: 1671 Cov.: 31 AF XY: 0.0465 AC XY: 33772 AN XY: 726554

Gnomad4 AFR exome AF: 0.00619

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.0773

Gnomad4 SAS exome AF: 0.0663

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0456

Gnomad4 OTH exome AF: 0.0428

GnomAD4 genome AF: 0.0334 AC: 5087 AN: 152212 Hom.: 107 Cov.: 32 AF XY: 0.0335 AC XY: 2494 AN XY: 74422

Gnomad4 AFR AF: 0.00773

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.0645

Gnomad4 SAS AF: 0.0695

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0445

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0385 Hom.: 69

Bravo AF: 0.0308

Asia WGS AF: 0.0600 AC: 208 AN: 3476

EpiCase AF: 0.0461

EpiControl AF: 0.0485

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	3.3
Dann	Benign	0.49

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: rs77738279; hg19: chr11-103006557; COSMIC: COSV62089578;