19-40576949-C-G

Variant names:

• chr19-40576949-C-G
• rs2081217072
• NM_138392.4:c.50C>G

Variant summary

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

The NM_138392.4(SHKBP1):​c.50C>G​(p.Pro17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,350,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P17H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: SHKBP1 NM_138392.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• Publications: 0 publications found

Genes affected

SHKBP1 (HGNC:19214): (SH3KBP1 binding protein 1) Enables identical protein binding activity. Predicted to be involved in positive regulation of epidermal growth factor receptor signaling pathway. Predicted to be located in lysosome. [provided by Alliance of Genome Resources, Apr 2022]

SHKBP1 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000301801 (HGNC:):

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=0.26595002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138392.4. 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
	SHKBP1	NM_138392.4	MANE Select	c.50C>G	p.Pro17Arg	missense	Exon 1 of 18	NP_612401.2	Q8TBC3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHKBP1	ENST00000291842.10	TSL:1 MANE Select	c.50C>G	p.Pro17Arg	missense	Exon 1 of 18	ENSP00000291842.4	Q8TBC3-1
	SHKBP1	ENST00000943564.1		c.50C>G	p.Pro17Arg	missense	Exon 1 of 19	ENSP00000613623.1
	SHKBP1	ENST00000869177.1		c.50C>G	p.Pro17Arg	missense	Exon 1 of 18	ENSP00000539236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1350520 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 664108

African (AFR) AF: 0.00 AC: 0 AN: 28908

American (AMR) AF: 0.00 AC: 0 AN: 22644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20576

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35554

South Asian (SAS) AF: 0.00 AC: 0 AN: 70670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062400

Other (OTH) AF: 0.00 AC: 0 AN: 55322

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.079
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.31		Gain of MoRF binding (P = 0.0147)
MVP		0.58
MPC		2.0
ClinPred		0.96	D
GERP RS		4.5
PromoterAI		0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.43
gMVP		0.53
Mutation Taster		=87/13	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

dbSNP: rs2081217072; hg19: chr19-41082855;