4-56821553-C-A

Variant names:

• chr4-56821553-C-A
• rs781544
• NM_001271718.2:c.110G>T

Variant summary

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

The NM_001271718.2(SPINK2):​c.110G>T​(p.Gly37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G37E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SPINK2 NM_001271718.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 0 publications found

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)

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK2	NM_001271718.2	MANE Select	c.110G>T	p.Gly37Val	missense	Exon 1 of 4	NP_001258647.1	D6RI10
	SPINK2	NM_001271722.2		c.110G>T	p.Gly37Val	missense	Exon 1 of 2	NP_001258651.1	A0A087WTA9
	SPINK2	NM_001271720.2		c.110G>T	p.Gly37Val	missense	Exon 1 of 4	NP_001258649.1	D6RC51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK2	ENST00000506738.6	TSL:2 MANE Select	c.110G>T	p.Gly37Val	missense	Exon 1 of 4	ENSP00000425961.1	D6RI10
	SPINK2	ENST00000248701.8	TSL:1	c.55+55G>T		intron	N/A	ENSP00000248701.4	P20155
	SPINK2	ENST00000618802.3	TSL:3	c.110G>T	p.Gly37Val	missense	Exon 1 of 2	ENSP00000477722.1	A0A087WTA9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394798 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 687934

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31400

American (AMR) AF: 0.00 AC: 0 AN: 35622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35696

South Asian (SAS) AF: 0.00 AC: 0 AN: 79042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078592

Other (OTH) AF: 0.00 AC: 0 AN: 57812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.71	T
PhyloP100		-0.21
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.053
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.15
MutPred		0.18		Gain of sheet (P = 0.0028)
MVP		0.17
ClinPred		0.090	T
GERP RS		-0.11
PromoterAI		0.24	Neutral
gMVP		0.34
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781544; hg19: chr4-57687719;