4-56809985-C-CT

Variant names:

• chr4-56809985-C-CT
• rs150309687
• NM_001271718.2:c.*153dupA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001271722.2(SPINK2):​c.404dupA​(p.Ter135fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,500,592 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (12 hom.)
• Consequence: SPINK2 NM_001271722.2 frameshift
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.375
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 4-56809985-C-CT is Benign according to our data. Variant chr4-56809985-C-CT is described in ClinVar as Benign. ClinVar VariationId is 3055956.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00666 (1014/152190) while in subpopulation AFR AF = 0.0224 (928/41520). AF 95% confidence interval is 0.0212. There are 14 homozygotes in GnomAd4. There are 478 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271722.2. 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.*153dupA		3_prime_UTR	Exon 4 of 4	NP_001258647.1	D6RI10
	SPINK2	NM_001271722.2		c.404dupA	p.Ter135fs	frameshift	Exon 2 of 2	NP_001258651.1	A0A087WTA9
	SPINK2	NM_001271720.2		c.*153dupA		3_prime_UTR	Exon 4 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.*153dupA		3_prime_UTR	Exon 4 of 4	ENSP00000425961.1	D6RI10
	SPINK2	ENST00000248701.8	TSL:1	c.*153dupA		3_prime_UTR	Exon 4 of 4	ENSP00000248701.4	P20155
	SPINK2	ENST00000618802.3	TSL:3	c.404dupA	p.Ter135fs	frameshift	Exon 2 of 2	ENSP00000477722.1	A0A087WTA9

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1015 AN: 152072 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00708

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000935 AC: 1261 AN: 1348402 Hom.: 12 Cov.: 30 AF XY: 0.00103 AC XY: 684 AN XY: 663834

African (AFR) AF: 0.0225 AC: 631 AN: 28062

American (AMR) AF: 0.00192 AC: 36 AN: 18724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23096

East Asian (EAS) AF: 0.00 AC: 0 AN: 34242

South Asian (SAS) AF: 0.00591 AC: 417 AN: 70584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48606

Middle Eastern (MID) AF: 0.00127 AC: 7 AN: 5514

European-Non Finnish (NFE) AF: 0.0000404 AC: 43 AN: 1063738

Other (OTH) AF: 0.00227 AC: 127 AN: 55836

GnomAD4 genome AF: 0.00666 AC: 1014 AN: 152190 Hom.: 14 Cov.: 32 AF XY: 0.00643 AC XY: 478 AN XY: 74392

African (AFR) AF: 0.0224 AC: 928 AN: 41520

American (AMR) AF: 0.00282 AC: 43 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00708 AC: 34 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00753

Asia WGS AF: 0.00577 AC: 20 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
PhyloP100		0.38
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: rs150309687; hg19: chr4-57676151;