Genetic Variant SPINK2:p.Ala18Pro (chr4-56821611-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001271718.2(SPINK2):c.52G>C(p.Ala18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A18T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPINK2
NM_001271718.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.295

Publications

0 publications found

Variant links:

Genes affected

SPINK2 (HGNC:11245): (serine peptidase inhibitor Kazal type 2) This gene encodes a member of the family of serine protease inhibitors of the Kazal type (SPINK). The encoded protein acts as a trypsin and acrosin inhibitor in the genital tract and is localized in the spermatozoa. The protein has been associated with the progression of lymphomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

SPINK2 Gene-Disease associations (from GenCC):

spermatogenic failure 29
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

SPINK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271718.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK2	NM_001271718.2	MANE Select	c.52G>C	p.Ala18Pro	missense	Exon 1 of 4	NP_001258647.1	D6RI10
SPINK2	NM_001271722.2		c.52G>C	p.Ala18Pro	missense	Exon 1 of 2	NP_001258651.1	A0A087WTA9
SPINK2	NM_001271720.2		c.52G>C	p.Ala18Pro	missense	Exon 1 of 4	NP_001258649.1	D6RC51

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK2	ENST00000506738.6	TSL:2 MANE Select	c.52G>C	p.Ala18Pro	missense	Exon 1 of 4	ENSP00000425961.1	D6RI10
SPINK2	ENST00000248701.8	TSL:1	c.52G>C	p.Ala18Pro	missense	Exon 1 of 4	ENSP00000248701.4	P20155
SPINK2	ENST00000618802.3	TSL:3	c.52G>C	p.Ala18Pro	missense	Exon 1 of 2	ENSP00000477722.1	A0A087WTA9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689596

African (AFR)

AF:

0.00

AC:

AN:

31478

American (AMR)

AF:

0.00

AC:

AN:

36216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35820

South Asian (SAS)

AF:

0.00

AC:

AN:

79192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5188

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079612

Other (OTH)

AF:

0.00

AC:

AN:

57926

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000225

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.26

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.43

PhyloP100

0.29

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.46

Sift

Benign

0.14

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.31

MutPred

0.65

Loss of helix (P = 0.0041)

MVP

0.56

MPC

0.57

ClinPred

0.85

GERP RS

1.9

PromoterAI

0.047

Neutral

(source)

Varity_R

0.39

gMVP

0.49

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over