11-103286264-C-T

Variant names:

• chr11-103286264-C-T
• rs769053227
• NM_001080463.2:c.10921C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001080463.2(DYNC2H1):​c.10921C>T​(p.Pro3641Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P3641P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:3 U:1
• Conservation: PhyloP100: 5.88
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.10921C>T	p.Pro3641Ser	missense	Exon 75 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.10900C>T	p.Pro3634Ser	missense	Exon 74 of 89	NP_001368.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.10921C>T	p.Pro3641Ser	missense	Exon 75 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.10900C>T	p.Pro3634Ser	missense	Exon 74 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2206-149679C>T		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248336 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461200 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726850

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111686

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

DYNC2H1-related disorder Pathogenic:1

May 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DYNC2H1 c.10921C>T variant is predicted to result in the amino acid substitution p.Pro3641Ser. This variant along with another DYNC2H1 truncating variant was reported in one patient with asphyxiating thoracic dystrophy (see Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.00089% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

not specified Uncertain:1

Aug 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DYNC2H1 c.10921C>T (p.Pro3641Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248336 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10921C>T has been reported in the literature as a compound heterozygous genotype together with a pathogenic variant in a neonate affected with Short-rib thoracic dysplasia (asphyxiating thoracic dystrophy) (Zhang_2018). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). No clinical diagnostic laboratories have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.46		Gain of helix (P = 0.0696)
MVP		0.58
MPC		0.33
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.69
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs769053227; hg19: chr11-103156993;