Genetic Variant SH2D6:p.Arg290Leu (chr2-85435802-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001394463.1(SH2D6):c.869G>T(p.Arg290Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R290Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SH2D6
NM_001394463.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.91

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

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.869G>T	p.Arg290Leu	missense	Exon 22 of 24	NP_001381392.1	Q7Z4S9-3
	SH2D6	NR_172131.1		n.1607G>T		non_coding_transcript_exon	Exon 19 of 21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D6	ENST00000469800.7	TSL:3 MANE Select	c.869G>T	p.Arg290Leu	missense	Exon 22 of 24	ENSP00000510308.1	Q7Z4S9-3
SH2D6	ENST00000340326.2	TSL:1	n.550G>T		non_coding_transcript_exon	Exon 3 of 5
SH2D6	ENST00000389938.7	TSL:1	n.*319G>T		non_coding_transcript_exon	Exon 19 of 21	ENSP00000374588.3	Q7Z4S9-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445938

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718104

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33248

American (AMR)

AF:

0.00

AC:

AN:

42118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25690

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39088

South Asian (SAS)

AF:

0.00

AC:

AN:

84358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104502

Other (OTH)

AF:

0.0000168

AC:

AN:

59686

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.61

PhyloP100

1.9

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.55

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Vest4

0.64

MVP

0.80

ClinPred

1.0

GERP RS

3.4

Mutation Taster

=79/21

polymorphism

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over