rs185916947

Variant names:

• chr11-103321019-A-T
• rs185916947
• NM_001080463.2:c.11747-10A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080463.2(DYNC2H1):​c.11747-10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,578,856 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (4 hom.)
• Consequence: DYNC2H1 NM_001080463.2 intron
• Scores: Splicing: ADA: 0.00001172
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.160
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-103321019-A-T is Benign according to our data. Variant chr11-103321019-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 439627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00517 (787/152254) while in subpopulation AFR AF = 0.0174 (722/41558). AF 95% confidence interval is 0.0163. There are 5 homozygotes in GnomAd4. There are 384 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.11747-10A>T		intron_variant	Intron 81 of 89	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.11726-10A>T		intron_variant	Intron 80 of 88	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.11747-10A>T		intron_variant	Intron 81 of 89		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.11726-10A>T		intron_variant	Intron 80 of 88	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2206-114924A>T		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
DYNC2H1	ENST00000528670.5	n.905-10A>T		intron_variant	Intron 8 of 16	5		ENSP00000433451.1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152136 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00130 AC: 283 AN: 217264 AF XY: 0.000918

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.000847

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.000761

GnomAD4 exome AF: 0.000574 AC: 819 AN: 1426602 Hom.: 4 Cov.: 30 AF XY: 0.000512 AC XY: 362 AN XY: 707622

African (AFR) AF: 0.0165 AC: 526 AN: 31848

American (AMR) AF: 0.00111 AC: 43 AN: 38568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39190

South Asian (SAS) AF: 0.000113 AC: 9 AN: 79510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52432

Middle Eastern (MID) AF: 0.00238 AC: 12 AN: 5046

European-Non Finnish (NFE) AF: 0.000141 AC: 155 AN: 1096292

Other (OTH) AF: 0.00126 AC: 74 AN: 58756

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152254 Hom.: 5 Cov.: 32 AF XY: 0.00516 AC XY: 384 AN XY: 74450

African (AFR) AF: 0.0174 AC: 722 AN: 41558

American (AMR) AF: 0.00288 AC: 44 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67984

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00550

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 07, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jeune thoracic dystrophy Benign:1

Jan 22, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.53
DANN	Benign	0.53
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
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: rs185916947; hg19: chr11-103191748;