rs781544

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-56821553-C-T
• chr4-56821553-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001271718.2(SPINK2):​c.110G>A​(p.Gly37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,546,526 control chromosomes in the GnomAD database, including 13,192 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (5370 hom., cov: 33)
  • Exomes 𝑓: 0.075 (7822 hom.)
• Consequence: SPINK2 NM_001271718.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.211
• Publications: 4 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8876791E-4).
• BP6: Variant 4-56821553-C-T is Benign according to our data. Variant chr4-56821553-C-T is described in ClinVar as Benign. ClinVar VariationId is 3059829.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

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>A	p.Gly37Glu	missense	Exon 1 of 4	NP_001258647.1	D6RI10
	SPINK2	NM_001271722.2		c.110G>A	p.Gly37Glu	missense	Exon 1 of 2	NP_001258651.1	A0A087WTA9
	SPINK2	NM_001271720.2		c.110G>A	p.Gly37Glu	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>A	p.Gly37Glu	missense	Exon 1 of 4	ENSP00000425961.1	D6RI10
	SPINK2	ENST00000248701.8	TSL:1	c.55+55G>A		intron	N/A	ENSP00000248701.4	P20155
	SPINK2	ENST00000618802.3	TSL:3	c.110G>A	p.Gly37Glu	missense	Exon 1 of 2	ENSP00000477722.1	A0A087WTA9

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29045 AN: 151888 Hom.: 5353 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.0879

Gnomad EAS AF: 0.0846

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.115 AC: 16235 AN: 141022 AF XY: 0.0996

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.0967

Gnomad EAS exome AF: 0.0875

Gnomad FIN exome AF: 0.0613

Gnomad NFE exome AF: 0.0588

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0746 AC: 103988 AN: 1394522 Hom.: 7822 Cov.: 32 AF XY: 0.0712 AC XY: 48936 AN XY: 687778

African (AFR) AF: 0.489 AC: 15350 AN: 31364

American (AMR) AF: 0.262 AC: 9328 AN: 35536

Ashkenazi Jewish (ASJ) AF: 0.0951 AC: 2392 AN: 25156

East Asian (EAS) AF: 0.0784 AC: 2797 AN: 35686

South Asian (SAS) AF: 0.0293 AC: 2313 AN: 79042

European-Finnish (FIN) AF: 0.0591 AC: 2765 AN: 46770

Middle Eastern (MID) AF: 0.0962 AC: 446 AN: 4636

European-Non Finnish (NFE) AF: 0.0585 AC: 63041 AN: 1078524

Other (OTH) AF: 0.0961 AC: 5556 AN: 57808

GnomAD4 genome AF: 0.191 AC: 29089 AN: 152004 Hom.: 5370 Cov.: 33 AF XY: 0.188 AC XY: 13940 AN XY: 74288

African (AFR) AF: 0.476 AC: 19674 AN: 41312

American (AMR) AF: 0.220 AC: 3368 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0879 AC: 305 AN: 3470

East Asian (EAS) AF: 0.0842 AC: 436 AN: 5176

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4824

European-Finnish (FIN) AF: 0.0705 AC: 749 AN: 10624

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0580 AC: 3942 AN: 67998

Other (OTH) AF: 0.174 AC: 367 AN: 2110

Alfa AF: 0.106 Hom.: 514

Bravo AF: 0.223

TwinsUK AF: 0.0491 AC: 182

ALSPAC AF: 0.0589 AC: 227

ExAC AF: 0.0537 AC: 3530

Asia WGS AF: 0.0820 AC: 285 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SPINK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.21
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.056
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.17
ClinPred		0.015	T
GERP RS		-0.11
PromoterAI		-0.011	Neutral
gMVP		0.33
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs781544; hg19: chr4-57687719; COSMIC: COSV99954259; COSMIC: COSV99954259;