Genetic Variant NM_001103161.2:c.895G>C (chr1-20723639-C-G) – 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_001103161.2(SH2D5):c.895G>C(p.Ala299Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,316 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. A299T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SH2D5
NM_001103161.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.667

Publications

0 publications found

Variant links:

Genes affected

SH2D5 (HGNC:28819): (SH2 domain containing 5) Predicted to be active in postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

SH2D5 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, 0.885

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103161.2. 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
	SH2D5	NM_001103161.2	MANE Select	c.895G>C	p.Ala299Pro	missense	Exon 8 of 10	NP_001096631.1	Q6ZV89-1
	SH2D5	NM_001103160.2		c.643G>C	p.Ala215Pro	missense	Exon 7 of 9	NP_001096630.1	Q6ZV89-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D5	ENST00000444387.7	TSL:2 MANE Select	c.895G>C	p.Ala299Pro	missense	Exon 8 of 10	ENSP00000406026.2	Q6ZV89-1
SH2D5	ENST00000870131.1		c.895G>C	p.Ala299Pro	missense	Exon 9 of 11	ENSP00000540190.1
SH2D5	ENST00000870132.1		c.895G>C	p.Ala299Pro	missense	Exon 9 of 11	ENSP00000540191.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

245758

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460316

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000448

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111730

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.095

Eigen

Benign

0.13

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.79

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.4

PhyloP100

0.67

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.35

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.033

Polyphen

0.94

Vest4

0.78

MutPred

0.80

Loss of glycosylation at S302 (P = 0.1891)

MVP

0.79

MPC

0.36

ClinPred

0.72

GERP RS

2.1

Varity_R

0.50

gMVP

0.69

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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