rs117178504

Positions:

• chr11-103283059-C-A
• chr11-103283059-C-G
• chr11-103283059-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The ENST00000375735.7(DYNC2H1):​c.10864C>A​(p.Arg3622=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,607,294 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: DYNC2H1 ENST00000375735.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.170

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 11-103283059-C-A is Benign according to our data. Variant chr11-103283059-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 220090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103283059-C-A is described in Lovd as [Benign]. Variant chr11-103283059-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.17 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.10885C>A	p.Arg3629=	synonymous_variant	74/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.10864C>A	p.Arg3622=	synonymous_variant	73/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.10885C>A	p.Arg3629=	synonymous_variant	74/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.10864C>A	p.Arg3622=	synonymous_variant	73/89	1	NM_001377.3	ENSP00000364887	P3
	ENST00000649070.1	n.690+9957G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1161 AN: 151942 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00699 AC: 1722 AN: 246432 Hom.: 7 AF XY: 0.00688 AC XY: 920 AN XY: 133790

Gnomad AFR exome AF: 0.00254

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00911

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000729

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00907

GnomAD4 exome AF: 0.0109 AC: 15878 AN: 1455232 Hom.: 105 Cov.: 30 AF XY: 0.0105 AC XY: 7577 AN XY: 723560

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00934

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000459

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00764 AC: 1161 AN: 152062 Hom.: 6 Cov.: 32 AF XY: 0.00698 AC XY: 519 AN XY: 74346

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00872 Hom.: 5

Bravo AF: 0.00914

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2018	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 08, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DYNC2H1: BP4, BP7, BS1, BS2 -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Asphyxiating thoracic dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	6.0
DANN	Benign	0.75

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: rs117178504; hg19: chr11-103153788;