4-56820582-G-C

Variant names:

• chr4-56820582-G-C
• rs577163578
• NM_001271718.2:c.206-3C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001271718.2(SPINK2):​c.206-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,606,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPINK2 NM_001271718.2 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.511
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-56820582-G-C is Pathogenic according to our data. Variant chr4-56820582-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 559843.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK2	NM_001271718.2	MANE Select	c.206-3C>G		splice_region intron	N/A	NP_001258647.1
	SPINK2	NM_001271722.2		c.205+876C>G		intron	N/A	NP_001258651.1
	SPINK2	NM_001271720.2		c.161-3C>G		splice_region intron	N/A	NP_001258649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK2	ENST00000506738.6	TSL:2 MANE Select	c.206-3C>G		splice_region intron	N/A	ENSP00000425961.1
	SPINK2	ENST00000248701.8	TSL:1	c.56-3C>G		splice_region intron	N/A	ENSP00000248701.4
	SPINK2	ENST00000618802.3	TSL:3	c.205+876C>G		intron	N/A	ENSP00000477722.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455024 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724346

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5020

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106738

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151948 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74190

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 29 Pathogenic:1

May 20, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.66
PhyloP100		0.51
Mutation Taster		=52/48	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: -1
DS_AL_spliceai		0.95		Position offset: -3

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

Other links and lift over

dbSNP: rs577163578; hg19: chr4-57686748;