rs1555076936

Variant names:

• chr11-103235718-A-G
• rs1555076936
• NM_001080463.2:c.9614A>G

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.9614A>G​(p.Gln3205Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.9614A>G	p.Gln3205Arg	missense_variant	Exon 62 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.9614A>G	p.Gln3205Arg	missense_variant	Exon 62 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.9614A>G	p.Gln3205Arg	missense_variant	Exon 62 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.9614A>G	p.Gln3205Arg	missense_variant	Exon 62 of 89	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	c.2205+101299A>G		intron_variant	Intron 15 of 19	1		ENSP00000334021.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Micrognathia;C0426790:Narrow chest;C0426817:Short ribs;C1854912:Short long bone;C4551485:Clinodactyly Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PhyloP100		6.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.0	N;.;.;N
REVEL	Uncertain	0.41
Sift	Benign	0.072	T;.;.;T
Sift4G	Uncertain	0.027	D;.;.;D
Polyphen		0.77	P;P;P;P
Vest4		0.61
MutPred		0.53		Gain of methylation at Q3205 (P = 0.0172);Gain of methylation at Q3205 (P = 0.0172);Gain of methylation at Q3205 (P = 0.0172);Gain of methylation at Q3205 (P = 0.0172);
MVP		0.72
MPC		0.14
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.67
gMVP		0.64
Mutation Taster		=63/37	polymorphism

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: rs1555076936; hg19: chr11-103106447;