rs648387

Positions:

• chr11-103253270-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):​c.10064-15G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,571,088 control chromosomes in the GnomAD database, including 117,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12447 hom., cov: 31)
  • Exomes 𝑓: 0.38 (105351 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.97

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-103253270-G-T is Benign according to our data. Variant chr11-103253270-G-T is described in ClinVar as [Benign]. Clinvar id is 93527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103253270-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.10064-15G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000650373.2
DYNC2H1	NM_001377.3	c.10043-15G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000375735.7	c.10043-15G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001377.3	P3
DYNC2H1	ENST00000650373.2	c.10064-15G>T		splice_polypyrimidine_tract_variant, intron_variant			NM_001080463.2	A1
DYNC2H1	ENST00000334267.11	c.2205+118851G>T		intron_variant		1
	ENST00000649070.1	n.691-966C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60708 AN: 151432 Hom.: 12431 Cov.: 31

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.362 AC: 84744 AN: 234080 Hom.: 15430 AF XY: 0.365 AC XY: 46389 AN XY: 126926

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.445

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.381 AC: 540843 AN: 1419540 Hom.: 105351 Cov.: 30 AF XY: 0.383 AC XY: 269602 AN XY: 704420

Gnomad4 AFR exome AF: 0.465

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.401 AC: 60755 AN: 151548 Hom.: 12447 Cov.: 31 AF XY: 0.401 AC XY: 29656 AN XY: 74032

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.449

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.392

Alfa AF: 0.294 Hom.: 1384

Bravo AF: 0.397

Asia WGS AF: 0.447 AC: 1553 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Eurofins Ntd Llc (ga)	Aug 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

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 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 Benign:1

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	-0.96
CADD	Benign	0.14
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: rs648387; hg19: chr11-103123999; COSMIC: COSV62106412;