rs6875902

Variant names:

• chr5-149028330-C-A
• rs6875902
• NM_024577.4:c.1402G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-149028330-C-A
• chr5-149028330-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024577.4(SH3TC2):​c.1402G>T​(p.Ala468Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,826 control chromosomes in the GnomAD database, including 36,254 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (4316 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31938 hom.)
• Consequence: SH3TC2 NM_024577.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.01
• Publications: 31 publications found

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), Orphanet, Ambry Genetics
• susceptibility to mononeuropathy of the median nerve, mild

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043907464).
• BP6: Variant 5-149028330-C-A is Benign according to our data. Variant chr5-149028330-C-A is described in ClinVar as Benign. ClinVar VariationId is 130297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	NM_024577.4	MANE Select	c.1402G>T	p.Ala468Ser	missense	Exon 11 of 17	NP_078853.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3TC2	ENST00000515425.6	TSL:1 MANE Select	c.1402G>T	p.Ala468Ser	missense	Exon 11 of 17	ENSP00000423660.1
	SH3TC2	ENST00000512049.5	TSL:1	c.1381G>T	p.Ala461Ser	missense	Exon 11 of 17	ENSP00000421860.1
	SH3TC2	ENST00000323829.9	TSL:1	n.*790G>T		non_coding_transcript_exon	Exon 12 of 18	ENSP00000313025.5

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34207 AN: 152012 Hom.: 4313 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.228

GnomAD2 exomes AF: 0.194 AC: 48653 AN: 251050 AF XY: 0.200

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.0245

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.204 AC: 298174 AN: 1461696 Hom.: 31938 Cov.: 80 AF XY: 0.206 AC XY: 149861 AN XY: 727142

African (AFR) AF: 0.312 AC: 10449 AN: 33480

American (AMR) AF: 0.120 AC: 5360 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6350 AN: 26136

East Asian (EAS) AF: 0.0374 AC: 1486 AN: 39700

South Asian (SAS) AF: 0.249 AC: 21448 AN: 86258

European-Finnish (FIN) AF: 0.179 AC: 9536 AN: 53240

Middle Eastern (MID) AF: 0.280 AC: 1613 AN: 5766

European-Non Finnish (NFE) AF: 0.206 AC: 229585 AN: 1111998

Other (OTH) AF: 0.204 AC: 12347 AN: 60394

GnomAD4 genome AF: 0.225 AC: 34222 AN: 152130 Hom.: 4316 Cov.: 32 AF XY: 0.224 AC XY: 16642 AN XY: 74382

African (AFR) AF: 0.309 AC: 12826 AN: 41492

American (AMR) AF: 0.159 AC: 2424 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3470

East Asian (EAS) AF: 0.0265 AC: 137 AN: 5178

South Asian (SAS) AF: 0.237 AC: 1142 AN: 4818

European-Finnish (FIN) AF: 0.184 AC: 1947 AN: 10586

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.208 AC: 14121 AN: 67988

Other (OTH) AF: 0.232 AC: 490 AN: 2110

Alfa AF: 0.207 Hom.: 14864

Bravo AF: 0.222

TwinsUK AF: 0.216 AC: 800

ALSPAC AF: 0.209 AC: 807

ESP6500AA AF: 0.306 AC: 1347

ESP6500EA AF: 0.204 AC: 1752

ExAC AF: 0.201 AC: 24405

EpiCase AF: 0.218

EpiControl AF: 0.222

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Charcot-Marie-Tooth disease type 4C (2)
-	-	2	Susceptibility to mononeuropathy of the median nerve, mild (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.0
DANN	Benign	0.85
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.0
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.17
Sift	Benign	0.69	T
Sift4G	Benign	0.34	T
Polyphen		0.88	P
Vest4		0.11
MPC		0.045
ClinPred		0.0098	T
GERP RS		0.80
Varity_R		0.034
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6875902; hg19: chr5-148407893; COSMIC: COSV107397715; COSMIC: COSV107397715;