chr5-149027750-A-G

Position:

• chr5-149027750-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024577.4(SH3TC2):​c.1982T>C​(p.Leu661Pro) variant causes a missense change. 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.75

Genes affected

SH3TC2 (HGNC:29427): (SH3 domain and tetratricopeptide repeats 2) This gene encodes a protein with two N-terminal Src homology 3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs, and is a member of a small gene family. The gene product has been proposed to be an adapter or docking molecule. Mutations in this gene result in autosomal recessive Charcot-Marie-Tooth disease type 4C, a childhood-onset neurodegenerative disease characterized by demyelination of motor and sensory neurons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3TC2	NM_024577.4	c.1982T>C	p.Leu661Pro	missense_variant	11/17	ENST00000515425.6	NP_078853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3TC2	ENST00000515425.6	c.1982T>C	p.Leu661Pro	missense_variant	11/17	1	NM_024577.4	ENSP00000423660.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.97	D;.
Vest4		0.88
MutPred		0.82		Gain of disorder (P = 0.0065);.;
MVP		0.88
MPC		0.25
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.71

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: rs80338927; hg19: chr5-148407313;