rs1555071484

Variant names:

• chr11-103215755-T-C
• rs1555071484
• NM_001080463.2:c.8729T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001377.3(DYNC2H1):​c.8729T>C​(p.Leu2910Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 11-103215755-T-C is Pathogenic according to our data. Variant chr11-103215755-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446587.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.8729T>C	p.Leu2910Pro	missense_variant	Exon 55 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.8729T>C	p.Leu2910Pro	missense_variant	Exon 55 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.8729T>C	p.Leu2910Pro	missense_variant	Exon 55 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.8729T>C	p.Leu2910Pro	missense_variant	Exon 55 of 89	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2205+81336T>C		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
DYNC2H1	ENST00000533027.1	n.329T>C		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 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

- -

Jeune thoracic dystrophy Pathogenic:1

Sep 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 2910 of the DYNC2H1 protein (p.Leu2910Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of short-rib thoracic dysplasia with or without polydactyly (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446587). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.0	M;M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.3	D;.;.;D
REVEL	Pathogenic	0.77
Sift	Benign	0.040	D;.;.;D
Sift4G	Benign	0.24	T;.;.;T
Polyphen		1.0	D;D;D;D
Vest4		0.87
MutPred		0.55		Loss of stability (P = 0.0081);Loss of stability (P = 0.0081);Loss of stability (P = 0.0081);Loss of stability (P = 0.0081);
MVP		0.79
MPC		0.46
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555071484; hg19: chr11-103086484;