rs118191062

chr11-103155417-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001080463.2(DYNC2H1):c.3660T>C(p.Pro1220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,612,412 control chromosomes in the GnomAD database, including 461 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 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.022 (431 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.124

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-103155417-T-C is Benign according to our data. Variant chr11-103155417-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302028.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr11-103155417-T-C is described in Lovd as [Likely_benign]. Variant chr11-103155417-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.124 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0153 (2329/152062) while in subpopulation NFE AF= 0.024 (1626/67882). AF 95% confidence interval is 0.023. There are 30 homozygotes in gnomad4. There are 1127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.3660T>C	p.Pro1220=	synonymous_variant	25/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.3660T>C	p.Pro1220=	synonymous_variant	25/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3660T>C	p.Pro1220=	synonymous_variant	25/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.3660T>C	p.Pro1220=	synonymous_variant	25/89	1	NM_001377.3	P3

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2328 AN: 151948 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0164 AC: 4068 AN: 247908 Hom.: 58 AF XY: 0.0163 AC XY: 2193 AN XY: 134518

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00559

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00355

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0253

Gnomad OTH exome AF: 0.0169

GnomAD4 exome AF: 0.0221 AC: 32273 AN: 1460350 Hom.: 431 Cov.: 34 AF XY: 0.0215 AC XY: 15621 AN XY: 726440

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.00610

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00410

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0258

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0153 AC: 2329 AN: 152062 Hom.: 30 Cov.: 32 AF XY: 0.0152 AC XY: 1127 AN XY: 74358

Gnomad4 AFR AF: 0.00395

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0200 Hom.: 20

Bravo AF: 0.0142

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0259

EpiControl AF: 0.0256

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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. -

Short rib-polydactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.7
Dann	Benign	0.44

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: rs118191062; hg19: chr11-103026146; COSMIC: COSV62095203;