rs202082545

Positions:

• chr11-103152201-T-C
• chr11-103152201-T-G

Variant summary

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

The NM_001377.3(DYNC2H1):​c.3012T>C​(p.Gly1004Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,606,482 control chromosomes in the GnomAD database, including 14 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 0.0033 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: DYNC2H1 NM_001377.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.356

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=-0.53).
• BP6: Variant 11-103152201-T-C is Benign according to our data. Variant chr11-103152201-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302024.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4}.
• BP7: Synonymous conserved (PhyloP=0.356 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.3012T>C	p.Gly1004Gly	synonymous_variant	21/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.3012T>C	p.Gly1004Gly	synonymous_variant	21/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3012T>C	p.Gly1004Gly	synonymous_variant	21/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.3012T>C	p.Gly1004Gly	synonymous_variant	21/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 499 AN: 151314 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00113 AC: 273 AN: 241642 Hom.: 1 AF XY: 0.000922 AC XY: 121 AN XY: 131288

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000518 AC: 754 AN: 1455060 Hom.: 8 Cov.: 33 AF XY: 0.000547 AC XY: 396 AN XY: 723350

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.00100

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00330 AC: 500 AN: 151422 Hom.: 6 Cov.: 31 AF XY: 0.00318 AC XY: 235 AN XY: 73946

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00377

Asia WGS AF: 0.00116 AC: 4 AN: 3462

EpiCase AF: 0.000166

EpiControl AF: 0.0000601

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1 Benign:1

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

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2017	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	Eurofins Ntd Llc (ga)	Aug 24, 2017	- -

Short rib-polydactyly syndrome Uncertain:1

Uncertain significance, 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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202082545; hg19: chr11-103022930;