rs114989645

Variant names:

• chr4-56820569-G-A
• rs114989645
• NM_001271718.2:c.216C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001271718.2(SPINK2):​c.216C>T​(p.Ile72Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,609,610 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: SPINK2 NM_001271718.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.593
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-56820569-G-A is Benign according to our data. Variant chr4-56820569-G-A is described in ClinVar as Benign. ClinVar VariationId is 3053347.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.593 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.216C>T	p.Ile72Ile	synonymous	Exon 2 of 4	NP_001258647.1	D6RI10
	SPINK2	NM_001271720.2		c.171C>T	p.Ile57Ile	synonymous	Exon 2 of 4	NP_001258649.1	D6RC51
	SPINK2	NM_021114.4		c.66C>T	p.Ile22Ile	synonymous	Exon 2 of 4	NP_066937.1	P20155

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK2	ENST00000506738.6	TSL:2 MANE Select	c.216C>T	p.Ile72Ile	synonymous	Exon 2 of 4	ENSP00000425961.1	D6RI10
	SPINK2	ENST00000248701.8	TSL:1	c.66C>T	p.Ile22Ile	synonymous	Exon 2 of 4	ENSP00000248701.4	P20155
	SPINK2	ENST00000504762.1	TSL:2	c.171C>T	p.Ile57Ile	synonymous	Exon 2 of 4	ENSP00000423858.1	D6RC51

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152132 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000990 AC: 249 AN: 251436 AF XY: 0.000692

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000386 AC: 562 AN: 1457366 Hom.: 2 Cov.: 29 AF XY: 0.000324 AC XY: 235 AN XY: 725334

African (AFR) AF: 0.0151 AC: 502 AN: 33334

American (AMR) AF: 0.000291 AC: 13 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000193 AC: 1 AN: 5182

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108646

Other (OTH) AF: 0.000681 AC: 41 AN: 60202

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152244 Hom.: 3 Cov.: 33 AF XY: 0.00351 AC XY: 261 AN XY: 74426

African (AFR) AF: 0.0138 AC: 572 AN: 41560

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00443

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.55
PhyloP100		-0.59
Mutation Taster		=100/0	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: rs114989645; hg19: chr4-57686735; COSMIC: COSV50534063; COSMIC: COSV50534063;