chr5-149052214-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024577.4(SH3TC2):c.79A>G(p.Thr27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,062 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

SH3TC2
NM_024577.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7

Conservation

PhyloP100: -0.120

Publications

5 publications found

Variant links:

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]

SH3TC2 Gene-Disease associations (from GenCC):

autosomal recessive hereditary demyelinating motor and sensory neuropathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4C
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
susceptibility to mononeuropathy of the median nerve, mild
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia

SH3TC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00543043).

BP6

Variant 5-149052214-T-C is Benign according to our data. Variant chr5-149052214-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220296.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152326) while in subpopulation NFE AF = 0.00182 (124/68024). AF 95% confidence interval is 0.00156. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024577.4. 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
	SH3TC2	NM_024577.4	MANE Select	c.79A>G	p.Thr27Ala	missense	Exon 2 of 17	NP_078853.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.79A>G	p.Thr27Ala	missense	Exon 2 of 17	ENSP00000423660.1	Q8TF17-1
SH3TC2	ENST00000512049.5	TSL:1	c.79A>G	p.Thr27Ala	missense	Exon 2 of 17	ENSP00000421860.1	Q8TF17-5
SH3TC2	ENST00000323829.9	TSL:1	n.79A>G		non_coding_transcript_exon	Exon 2 of 18	ENSP00000313025.5	D6RA65

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00133

AC:

335

AN:

251358

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00178

AC:

2604

AN:

1460736

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1267

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33444

American (AMR)

AF:

0.000179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39666

South Asian (SAS)

AF:

0.00162

AC:

140

AN:

86232

European-Finnish (FIN)

AF:

0.00240

AC:

128

AN:

53374

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00202

AC:

2248

AN:

1111068

Other (OTH)

AF:

0.000895

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152326

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41570

American (AMR)

AF:

0.00111

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68024

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00131

AC:

159

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Charcot-Marie-Tooth disease (2)

not specified (2)

Charcot-Marie-Tooth disease type 4 (1)

Charcot-Marie-Tooth disease type 4C (1)

Inborn genetic diseases (1)

SH3TC2-related disorder (1)

Susceptibility to mononeuropathy of the median nerve, mild (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.021

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.054

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.39

M_CAP

Benign

0.014

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.63

PhyloP100

-0.12

PrimateAI

Benign

0.26

PROVEAN

Benign

0.060

REVEL

Benign

0.11

Sift

Benign

0.59

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.071

MVP

0.40

MPC

0.039

ClinPred

0.00078

GERP RS

-3.5

Varity_R

0.028

gMVP

0.12

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over