rs786204078

chr11-103156638-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001080463.2(DYNC2H1):c.3995T>G(p.Leu1332Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.3995T>G	p.Leu1332Arg	missense_variant	26/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.3995T>G	p.Leu1332Arg	missense_variant	26/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.3995T>G	p.Leu1332Arg	missense_variant	26/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.3995T>G	p.Leu1332Arg	missense_variant	26/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+22219T>G		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*1540T>G		3_prime_UTR_variant, NMD_transcript_variant	24/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461308 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2018

This variant has not been reported in the literature in individuals with DYNC2H1-related disease. ClinVar contains an entry for this variant (Variation ID: 188115). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 1332 of the DYNC2H1 protein (p.Leu1332Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.5	H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.2	D;.;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.90		Gain of ubiquitination at K1331 (P = 0.0401);Gain of ubiquitination at K1331 (P = 0.0401);Gain of ubiquitination at K1331 (P = 0.0401);Gain of ubiquitination at K1331 (P = 0.0401);
MVP		0.85
MPC		0.45
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs786204078; hg19: chr11-103027367;