rs201016942

Positions:

• chr11-103166005-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001080463.2(DYNC2H1):​c.4719A>G​(p.Gln1573=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000684 in 1,534,834 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (13 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0720

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 11-103166005-A-G is Benign according to our data. Variant chr11-103166005-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 459280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103166005-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.072 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.4719A>G	p.Gln1573=	synonymous_variant	31/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.4719A>G	p.Gln1573=	synonymous_variant	31/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.4719A>G	p.Gln1573=	synonymous_variant	31/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.4719A>G	p.Gln1573=	synonymous_variant	31/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+31586A>G		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000649323.1	c.*2264A>G		3_prime_UTR_variant, NMD_transcript_variant	29/51			ENSP00000497581

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152158 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00156 AC: 226 AN: 145290 Hom.: 4 AF XY: 0.00202 AC XY: 155 AN XY: 76650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.00191

Gnomad EAS exome AF: 0.0000990

Gnomad SAS exome AF: 0.00860

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000333

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000709 AC: 980 AN: 1382558 Hom.: 13 Cov.: 30 AF XY: 0.000958 AC XY: 652 AN XY: 680780

Gnomad4 AFR exome AF: 0.000193

Gnomad4 AMR exome AF: 0.000235

Gnomad4 ASJ exome AF: 0.00225

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152276 Hom.: 3 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.00722 AC: 25 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

DYNC2H1: BP4, BP7, BS2 -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.5
DANN	Benign	0.18

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: rs201016942; hg19: chr11-103036734;