rs376067770

Variant names:

• chr11-103253278-T-A
• rs376067770
• NM_001080463.2:c.10064-7T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001080463.2(DYNC2H1):​c.10064-7T>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 0.000409 in 1,596,504 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, intron
• Scores: Splicing: ADA: 0.001115
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.284
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-103253278-T-A is Benign according to our data. Variant chr11-103253278-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302086.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.10064-7T>A		splice_region_variant, intron_variant	Intron 66 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.10043-7T>A		splice_region_variant, intron_variant	Intron 65 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.10064-7T>A		splice_region_variant, intron_variant	Intron 66 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.10043-7T>A		splice_region_variant, intron_variant	Intron 65 of 88	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2205+118859T>A		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
ENSG00000285878	ENST00000649070.1	n.691-974A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000232 AC: 56 AN: 241178 AF XY: 0.000253

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000430 AC: 621 AN: 1444382 Hom.: 3 Cov.: 32 AF XY: 0.000400 AC XY: 287 AN XY: 716928

African (AFR) AF: 0.0000919 AC: 3 AN: 32646

American (AMR) AF: 0.0000232 AC: 1 AN: 43148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25602

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.000548 AC: 604 AN: 1103052

Other (OTH) AF: 0.000201 AC: 12 AN: 59570

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74316

African (AFR) AF: 0.0000724 AC: 3 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000215

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Uncertain:2

Oct 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DYNC2H1 c.10064-7T>A variant (rs376067770), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 302086). This variant is found in the non-Finnish European population with an allele frequency of 0.050% (63/125898 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. However, without functional studies the effect on splicing is unknown. Due to limited information, the clinical significance of the c.10064-7T>A variant is uncertain at this time. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1 Benign:1

Mar 02, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jeune thoracic dystrophy Uncertain:1 Benign:1

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.30
DANN	Benign	0.33
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.038
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: rs376067770; hg19: chr11-103124007; COSMIC: COSV62109441;