NM_001080463.2:c.12478-6C>T

Variant names:

• chr11-103455180-C-T
• rs11225812
• NM_001080463.2:c.12478-6C>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.12478-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 1,608,958 control chromosomes in the GnomAD database, including 6,590 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (424 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6166 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002026
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.628
• Publications: 7 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=-0.86).
• BP6: Variant 11-103455180-C-T is Benign according to our data. Variant chr11-103455180-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.12478-6C>T		splice_region_variant, intron_variant	Intron 86 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.12457-6C>T		splice_region_variant, intron_variant	Intron 85 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.12478-6C>T		splice_region_variant, intron_variant	Intron 86 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.12457-6C>T		splice_region_variant, intron_variant	Intron 85 of 88	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10435 AN: 152046 Hom.: 421 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.0591

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0988

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0933

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.0769 AC: 19086 AN: 248072 AF XY: 0.0787

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0535

Gnomad ASJ exome AF: 0.0774

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0938

Gnomad OTH exome AF: 0.0925

GnomAD4 exome AF: 0.0899 AC: 130931 AN: 1456794 Hom.: 6166 Cov.: 29 AF XY: 0.0891 AC XY: 64555 AN XY: 724852

African (AFR) AF: 0.0140 AC: 468 AN: 33348

American (AMR) AF: 0.0564 AC: 2519 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 2015 AN: 26054

East Asian (EAS) AF: 0.0715 AC: 2834 AN: 39610

South Asian (SAS) AF: 0.0610 AC: 5247 AN: 86030

European-Finnish (FIN) AF: 0.108 AC: 5742 AN: 53304

Middle Eastern (MID) AF: 0.0703 AC: 405 AN: 5762

European-Non Finnish (NFE) AF: 0.0964 AC: 106785 AN: 1107884

Other (OTH) AF: 0.0817 AC: 4916 AN: 60170

GnomAD4 genome AF: 0.0686 AC: 10440 AN: 152164 Hom.: 424 Cov.: 33 AF XY: 0.0697 AC XY: 5188 AN XY: 74384

African (AFR) AF: 0.0171 AC: 710 AN: 41552

American (AMR) AF: 0.0699 AC: 1068 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 250 AN: 3470

East Asian (EAS) AF: 0.0593 AC: 307 AN: 5180

South Asian (SAS) AF: 0.0647 AC: 312 AN: 4822

European-Finnish (FIN) AF: 0.0988 AC: 1047 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0933 AC: 6338 AN: 67942

Other (OTH) AF: 0.0866 AC: 183 AN: 2112

Alfa AF: 0.0790 Hom.: 844

Bravo AF: 0.0654

Asia WGS AF: 0.0450 AC: 158 AN: 3476

EpiCase AF: 0.0917

EpiControl AF: 0.0939

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 15, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Jeune thoracic dystrophy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

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. -

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.27
DANN	Benign	0.33
PhyloP100		-0.63
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs11225812; hg19: chr11-103325908; COSMIC: COSV104398127;