rs116888435

chr11-103120787-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080463.2(DYNC2H1):c.1233A>G(p.Gln411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,561,178 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.017 (232 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.352

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=-0.54).
• BP6: Variant 11-103120787-A-G is Benign according to our data. Variant chr11-103120787-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 302010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103120787-A-G is described in Lovd as [Likely_benign]. Variant chr11-103120787-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0142 (2160/152092) while in subpopulation AMR AF= 0.0225 (343/15272). AF 95% confidence interval is 0.0205. There are 26 homozygotes in gnomad4. There are 1019 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.1233A>G	p.Gln411=	synonymous_variant	8/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.1233A>G	p.Gln411=	synonymous_variant	8/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.1233A>G	p.Gln411=	synonymous_variant	8/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.1233A>G	p.Gln411=	synonymous_variant	8/89	1	NM_001377.3	P3

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2164 AN: 151976 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00961

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0160 AC: 2760 AN: 172070 Hom.: 38 AF XY: 0.0161 AC XY: 1492 AN XY: 92674

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0167 AC: 23592 AN: 1409086 Hom.: 232 Cov.: 31 AF XY: 0.0169 AC XY: 11770 AN XY: 697192

Gnomad4 AFR exome AF: 0.00343

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.0407

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.00942

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0185

GnomAD4 genome AF: 0.0142 AC: 2160 AN: 152092 Hom.: 26 Cov.: 32 AF XY: 0.0137 AC XY: 1019 AN XY: 74376

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00961

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0196 Hom.: 26

Bravo AF: 0.0148

Asia WGS AF: 0.00810 AC: 28 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Mar 03, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2017	- -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Short rib-polydactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	3.7
Dann	Benign	0.53

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: rs116888435; hg19: chr11-102991516;