rs192003811

Positions:

• chr11-103245271-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001080463.2(DYNC2H1):​c.9960T>C​(p.Ala3320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,544,904 control chromosomes in the GnomAD database, including 25 homozygotes. 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 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.08

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-103245271-T-C is Benign according to our data. Variant chr11-103245271-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302084.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr11-103245271-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.9960T>C	p.Ala3320=	synonymous_variant	66/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.9939T>C	p.Ala3313=	synonymous_variant	65/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.9960T>C	p.Ala3320=	synonymous_variant	66/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.9939T>C	p.Ala3313=	synonymous_variant	65/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+110852T>C		intron_variant		1		ENSP00000334021

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 484 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00271 AC: 428 AN: 157898 Hom.: 2 AF XY: 0.00267 AC XY: 222 AN XY: 83080

Gnomad AFR exome AF: 0.000966

Gnomad AMR exome AF: 0.000862

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000721

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00482 AC: 6707 AN: 1392668 Hom.: 25 Cov.: 29 AF XY: 0.00479 AC XY: 3291 AN XY: 686982

Gnomad4 AFR exome AF: 0.000700

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000598

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000693

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.00583

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.00319 AC: 485 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74428

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00524

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00429 Hom.: 1

Bravo AF: 0.00300

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	DYNC2H1: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	- -

Asphyxiating thoracic dystrophy 3 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.8
DANN	Benign	0.79

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: rs192003811; hg19: chr11-103116000;