Genetic Variant SPINK2:c.206-3C>G (chr4-56820582-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

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

Variant links:

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)

SPINK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPINK2	NM_001271718.2	MANE Select	c.206-3C>G	splice_region intron	N/A	NP_001258647.1	D6RI10
SPINK2	NM_001271722.2		c.205+876C>G	intron	N/A	NP_001258651.1	A0A087WTA9
SPINK2	NM_001271720.2		c.161-3C>G	splice_region intron	N/A	NP_001258649.1	D6RC51

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPINK2	ENST00000506738.6	TSL:2 MANE Select	c.206-3C>G	splice_region intron	N/A	ENSP00000425961.1	D6RI10
SPINK2	ENST00000248701.8	TSL:1	c.56-3C>G	splice_region intron	N/A	ENSP00000248701.4	P20155
SPINK2	ENST00000618802.3	TSL:3	c.205+876C>G	intron	N/A	ENSP00000477722.1	A0A087WTA9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

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:

AN:

1455024

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5020

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106738

Other (OTH)

AF:

0.00

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151948

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 29 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.51

Mutation Taster

=52/48

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over