rs10895417

Variant names:

• chr11-103399879-G-A
• rs10895417
• NM_001080463.2:c.12387+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-103399879-G-A
• chr11-103399879-G-C

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.12387+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,605,638 control chromosomes in the GnomAD database, including 180,693 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20164 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160529 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002362
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.20
• Publications: 15 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-103399879-G-A is Benign according to our data. Variant chr11-103399879-G-A is described in ClinVar as Benign. ClinVar VariationId is 302120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.12387+7G>A		splice_region_variant, intron_variant	Intron 85 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.12366+7G>A		splice_region_variant, intron_variant	Intron 84 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12387+7G>A		splice_region_variant, intron_variant	Intron 85 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.12366+7G>A		splice_region_variant, intron_variant	Intron 84 of 88	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77607 AN: 151962 Hom.: 20131 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.495

GnomAD2 exomes AF: 0.490 AC: 121112 AN: 247116 AF XY: 0.487

Gnomad AFR exome AF: 0.620

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.467 AC: 678353 AN: 1453558 Hom.: 160529 Cov.: 30 AF XY: 0.469 AC XY: 339169 AN XY: 723522

African (AFR) AF: 0.629 AC: 20943 AN: 33274

American (AMR) AF: 0.552 AC: 24604 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11864 AN: 26052

East Asian (EAS) AF: 0.564 AC: 22332 AN: 39612

South Asian (SAS) AF: 0.554 AC: 47600 AN: 85874

European-Finnish (FIN) AF: 0.414 AC: 22047 AN: 53282

Middle Eastern (MID) AF: 0.552 AC: 3173 AN: 5746

European-Non Finnish (NFE) AF: 0.450 AC: 496879 AN: 1105122

Other (OTH) AF: 0.481 AC: 28911 AN: 60062

GnomAD4 genome AF: 0.511 AC: 77688 AN: 152080 Hom.: 20164 Cov.: 32 AF XY: 0.514 AC XY: 38212 AN XY: 74324

African (AFR) AF: 0.617 AC: 25590 AN: 41488

American (AMR) AF: 0.537 AC: 8198 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1578 AN: 3468

East Asian (EAS) AF: 0.529 AC: 2734 AN: 5168

South Asian (SAS) AF: 0.545 AC: 2631 AN: 4824

European-Finnish (FIN) AF: 0.432 AC: 4564 AN: 10558

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30833 AN: 67988

Other (OTH) AF: 0.495 AC: 1044 AN: 2110

Alfa AF: 0.469 Hom.: 5575

Bravo AF: 0.518

Asia WGS AF: 0.567 AC: 1973 AN: 3476

EpiCase AF: 0.447

EpiControl AF: 0.441

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Asphyxiating thoracic dystrophy 3 Benign:2

Jan 13, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.67
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0040
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: rs10895417; hg19: chr11-103270607; COSMIC: COSV62095911; COSMIC: COSV62095911;