NM_001103161.2:c.886T>C

Variant names:

• chr1-20723648-A-G
• NM_001103161.2:c.886T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001103161.2(SH2D5):​c.886T>C​(p.Trp296Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SH2D5 NM_001103161.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

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.886T>C	p.Trp296Arg	missense	Exon 8 of 10	NP_001096631.1	Q6ZV89-1
	SH2D5	NM_001103160.2		c.634T>C	p.Trp212Arg	missense	Exon 7 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.886T>C	p.Trp296Arg	missense	Exon 8 of 10	ENSP00000406026.2	Q6ZV89-1
	SH2D5	ENST00000870131.1		c.886T>C	p.Trp296Arg	missense	Exon 9 of 11	ENSP00000540190.1
	SH2D5	ENST00000870132.1		c.886T>C	p.Trp296Arg	missense	Exon 9 of 11	ENSP00000540191.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460632 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726628

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60372

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.90		Gain of disorder (P = 0.019)
MVP		0.92
MPC		0.66
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.79
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

hg19: chr1-21050141;