rs781543

Variant names:

• chr4-56821545-T-C
• rs781543
• NM_001271718.2:c.118A>G

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.118A>G​(p.Thr40Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0861 in 1,545,832 control chromosomes in the GnomAD database, including 13,190 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 (5376 hom., cov: 33)
  • Exomes 𝑓: 0.075 (7814 hom.)
• Consequence: SPINK2 NM_001271718.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0700
• Publications: 3 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=2.2730231E-4).
• BP6: Variant 4-56821545-T-C is Benign according to our data. Variant chr4-56821545-T-C is described in ClinVar as Benign. ClinVar VariationId is 3058909.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.118A>G	p.Thr40Ala	missense	Exon 1 of 4	NP_001258647.1	D6RI10
	SPINK2	NM_001271722.2		c.118A>G	p.Thr40Ala	missense	Exon 1 of 2	NP_001258651.1	A0A087WTA9
	SPINK2	NM_001271720.2		c.118A>G	p.Thr40Ala	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.118A>G	p.Thr40Ala	missense	Exon 1 of 4	ENSP00000425961.1	D6RI10
	SPINK2	ENST00000248701.8	TSL:1	c.55+63A>G		intron	N/A	ENSP00000248701.4	P20155
	SPINK2	ENST00000618802.3	TSL:3	c.118A>G	p.Thr40Ala	missense	Exon 1 of 2	ENSP00000477722.1	A0A087WTA9

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29052 AN: 151846 Hom.: 5359 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.0847

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.115 AC: 16051 AN: 139724 AF XY: 0.0995

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.0966

Gnomad EAS exome AF: 0.0873

Gnomad FIN exome AF: 0.0604

Gnomad NFE exome AF: 0.0589

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0746 AC: 103941 AN: 1393872 Hom.: 7814 Cov.: 32 AF XY: 0.0712 AC XY: 48924 AN XY: 687500

African (AFR) AF: 0.489 AC: 15340 AN: 31346

American (AMR) AF: 0.263 AC: 9330 AN: 35530

Ashkenazi Jewish (ASJ) AF: 0.0951 AC: 2392 AN: 25152

East Asian (EAS) AF: 0.0784 AC: 2797 AN: 35672

South Asian (SAS) AF: 0.0293 AC: 2311 AN: 78982

European-Finnish (FIN) AF: 0.0584 AC: 2714 AN: 46444

Middle Eastern (MID) AF: 0.0962 AC: 432 AN: 4492

European-Non Finnish (NFE) AF: 0.0585 AC: 63066 AN: 1078456

Other (OTH) AF: 0.0962 AC: 5559 AN: 57798

GnomAD4 genome AF: 0.191 AC: 29096 AN: 151960 Hom.: 5376 Cov.: 33 AF XY: 0.188 AC XY: 13957 AN XY: 74292

African (AFR) AF: 0.476 AC: 19679 AN: 41302

American (AMR) AF: 0.220 AC: 3370 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 305 AN: 3472

East Asian (EAS) AF: 0.0843 AC: 436 AN: 5170

South Asian (SAS) AF: 0.0318 AC: 153 AN: 4818

European-Finnish (FIN) AF: 0.0706 AC: 749 AN: 10614

Middle Eastern (MID) AF: 0.121 AC: 35 AN: 290

European-Non Finnish (NFE) AF: 0.0580 AC: 3943 AN: 67986

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

Alfa AF: 0.118 Hom.: 482

Bravo AF: 0.223

TwinsUK AF: 0.0485 AC: 180

ALSPAC AF: 0.0586 AC: 226

ExAC AF: 0.0604 AC: 3528

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	0.063
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.4
DANN	Benign	0.60
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00093	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.00023	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.070
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	0.63	T
Vest4		0.066
ClinPred		0.0033	T
GERP RS		-0.79
PromoterAI		0.057	Neutral
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

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: rs781543; hg19: chr4-57687711; COSMIC: COSV99954257; COSMIC: COSV99954257;