rs648387

Variant names:

• chr11-103253270-G-T
• rs648387
• NM_001080463.2:c.10064-15G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080463.2(DYNC2H1):​c.10064-15G>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.97
• Publications: 5 publications found

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]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285878 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 93527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.10064-15G>T		intron	N/A	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.10043-15G>T		intron	N/A	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.10064-15G>T		intron	N/A	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.10043-15G>T		intron	N/A	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+118851G>T		intron	N/A	ENSP00000334021.7

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

GnomAD2 exomes AF: 0.362 AC: 84744 AN: 234080 AF XY: 0.365

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 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

African (AFR) AF: 0.465 AC: 14863 AN: 31958

American (AMR) AF: 0.238 AC: 10089 AN: 42446

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 8131 AN: 25230

East Asian (EAS) AF: 0.494 AC: 19335 AN: 39176

South Asian (SAS) AF: 0.433 AC: 34748 AN: 80188

European-Finnish (FIN) AF: 0.362 AC: 19007 AN: 52490

Middle Eastern (MID) AF: 0.353 AC: 1976 AN: 5602

European-Non Finnish (NFE) AF: 0.379 AC: 410308 AN: 1083876

Other (OTH) AF: 0.382 AC: 22386 AN: 58574

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

African (AFR) AF: 0.471 AC: 19465 AN: 41316

American (AMR) AF: 0.304 AC: 4630 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1125 AN: 3464

East Asian (EAS) AF: 0.449 AC: 2307 AN: 5140

South Asian (SAS) AF: 0.453 AC: 2177 AN: 4806

European-Finnish (FIN) AF: 0.369 AC: 3869 AN: 10474

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25768 AN: 67832

Other (OTH) AF: 0.392 AC: 825 AN: 2104

Alfa AF: 0.300 Hom.: 1469

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

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 08, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jeune thoracic dystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asphyxiating thoracic dystrophy 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.14
DANN	Benign	0.44
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs648387; hg19: chr11-103123999; COSMIC: COSV62106412;