NM_001103161.2:c.1268G>A

Variant names:

• chr1-20721796-C-T
• NM_001103161.2:c.1268G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001103161.2(SH2D5):​c.1268G>A​(p.Gly423Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SH2D5 NM_001103161.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2834607).

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.1268G>A	p.Gly423Asp	missense	Exon 10 of 10	NP_001096631.1	Q6ZV89-1
	SH2D5	NM_001103160.2		c.1016G>A	p.Gly339Asp	missense	Exon 9 of 9	NP_001096630.1	Q6ZV89-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D5	ENST00000444387.7	TSL:2 MANE Select	c.1268G>A	p.Gly423Asp	missense	Exon 10 of 10	ENSP00000406026.2	Q6ZV89-1
	SH2D5	ENST00000870131.1		c.1268G>A	p.Gly423Asp	missense	Exon 11 of 11	ENSP00000540190.1
	SH2D5	ENST00000870132.1		c.1268G>A	p.Gly423Asp	missense	Exon 11 of 11	ENSP00000540191.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414646 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 698874

African (AFR) AF: 0.00 AC: 0 AN: 32666

American (AMR) AF: 0.00 AC: 0 AN: 39376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24424

East Asian (EAS) AF: 0.00 AC: 0 AN: 38092

South Asian (SAS) AF: 0.00 AC: 0 AN: 81116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4530

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086646

Other (OTH) AF: 0.00 AC: 0 AN: 58222

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.25		Loss of helix (P = 0.0626)
MVP		0.51
MPC		0.60
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.46
gMVP		0.73
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr1-21048289;