rs886039812

Variant names:

• chr11-103155395-T-G
• rs886039812
• NM_001080463.2:c.3638T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001377.3(DYNC2H1):​c.3638T>G​(p.Leu1213Arg) 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: 32)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.64
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 11-103155395-T-G is Pathogenic according to our data. Variant chr11-103155395-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 266101.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.3638T>G	p.Leu1213Arg	missense	Exon 25 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.3638T>G	p.Leu1213Arg	missense	Exon 25 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.3638T>G	p.Leu1213Arg	missense	Exon 25 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.3638T>G	p.Leu1213Arg	missense	Exon 25 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+20976T>G		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Asphyxiating thoracic dystrophy 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.90		Gain of solvent accessibility (P = 0.0584)
MVP		0.78
MPC		0.45
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.90
Mutation Taster		=13/87	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: rs886039812; hg19: chr11-103026124; COSMIC: COSV62088371;