Genetic Variant NM_001394463.1:c.602C>T (chr2-85435077-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001394463.1(SH2D6):c.602C>T(p.Ser201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,367,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000078 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SH2D6
NM_001394463.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0430

Publications

2 publications found

Variant links:

Genes affected

SH2D6 (HGNC:30439): (SH2 domain containing 6) Predicted to be involved in intracellular signal transduction and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SH2D6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031116039).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394463.1. 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
	SH2D6	NM_001394463.1	MANE Select	c.602C>T	p.Ser201Leu	missense	Exon 20 of 24	NP_001381392.1	Q7Z4S9-3
	SH2D6	NR_172131.1		n.1424C>T		non_coding_transcript_exon	Exon 18 of 21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D6	ENST00000469800.7	TSL:3 MANE Select	c.602C>T	p.Ser201Leu	missense	Exon 20 of 24	ENSP00000510308.1	Q7Z4S9-3
SH2D6	ENST00000340326.2	TSL:1	n.283C>T		non_coding_transcript_exon	Exon 1 of 5
SH2D6	ENST00000389938.7	TSL:1	n.*136C>T		non_coding_transcript_exon	Exon 18 of 21	ENSP00000374588.3	Q7Z4S9-4

Frequencies

GnomAD3 genomes

AF:

0.0000782

AC:

AN:

127920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

245172

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.00000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1239398

Hom.:

Cov.:

AF XY:

0.0000163

AC XY:

AN XY:

614014

show subpopulations

African (AFR)

AF:

0.000333

AC:

AN:

27020

American (AMR)

AF:

0.0000528

AC:

AN:

37908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17778

East Asian (EAS)

AF:

0.00

AC:

AN:

19530

South Asian (SAS)

AF:

0.00

AC:

AN:

83844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34586

Middle Eastern (MID)

AF:

0.000253

AC:

AN:

3956

European-Non Finnish (NFE)

AF:

0.00000826

AC:

AN:

968994

Other (OTH)

AF:

0.0000437

AC:

AN:

45782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000782

AC:

AN:

127920

Hom.:

Cov.:

AF XY:

0.0000836

AC XY:

AN XY:

59820

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

34438

American (AMR)

AF:

0.00

AC:

AN:

9916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3326

East Asian (EAS)

AF:

0.00

AC:

AN:

3826

South Asian (SAS)

AF:

0.00

AC:

AN:

3812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63656

Other (OTH)

AF:

0.00

AC:

AN:

1752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000986

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.7

(source)

DANN

Benign

0.27

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.44

M_CAP

Benign

0.020

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.91

PhyloP100

-0.043

PrimateAI

Benign

0.28

PROVEAN

Benign

0.95

REVEL

Benign

0.12

Sift

Benign

0.34

Sift4G

Benign

0.33

Vest4

0.10

MVP

0.099

ClinPred

0.085

GERP RS

-1.4

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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