19-51000268-T-C

Variant names:

• chr19-51000268-T-C
• rs1701946
• NM_007196.4:c.231-10A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007196.4(KLK8):​c.231-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,566,868 control chromosomes in the GnomAD database, including 169,797 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (25461 hom., cov: 29)
  • Exomes 𝑓: 0.44 (144336 hom.)
• Consequence: KLK8 NM_007196.4 intron
• Scores: Splicing: ADA: 0.00002932
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 13 publications found

Genes affected

KLK8 (HGNC:6369): (kallikrein related peptidase 8) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in tandem in a gene cluster on chromosome 19. The encoded protein may be involved in proteolytic cascade in the skin and may serve as a biomarker for ovarian cancer. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ENSG00000267879 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007196.4. 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
	KLK8	NM_007196.4	MANE Select	c.231-10A>G		intron	N/A	NP_009127.1
	KLK8	NM_144505.3		c.366-10A>G		intron	N/A	NP_653088.1
	KLK8	NM_001281431.2		c.-133-10A>G		intron	N/A	NP_001268360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK8	ENST00000695909.1	MANE Select	c.231-10A>G		intron	N/A	ENSP00000512260.1
	KLK8	ENST00000391806.6	TSL:1	c.366-10A>G		intron	N/A	ENSP00000375682.1
	KLK8	ENST00000600767.5	TSL:2	c.231-10A>G		intron	N/A	ENSP00000472016.1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83458 AN: 151556 Hom.: 25417 Cov.: 29

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.547

GnomAD2 exomes AF: 0.472 AC: 106393 AN: 225524 AF XY: 0.455

Gnomad AFR exome AF: 0.832

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.445 AC: 629404 AN: 1415196 Hom.: 144336 Cov.: 43 AF XY: 0.439 AC XY: 305486 AN XY: 696094

African (AFR) AF: 0.845 AC: 27679 AN: 32754

American (AMR) AF: 0.566 AC: 24292 AN: 42896

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 11057 AN: 23598

East Asian (EAS) AF: 0.371 AC: 14454 AN: 39006

South Asian (SAS) AF: 0.324 AC: 25785 AN: 79684

European-Finnish (FIN) AF: 0.397 AC: 20070 AN: 50502

Middle Eastern (MID) AF: 0.463 AC: 2564 AN: 5532

European-Non Finnish (NFE) AF: 0.440 AC: 476100 AN: 1082872

Other (OTH) AF: 0.470 AC: 27403 AN: 58352

GnomAD4 genome AF: 0.551 AC: 83559 AN: 151672 Hom.: 25461 Cov.: 29 AF XY: 0.542 AC XY: 40184 AN XY: 74094

African (AFR) AF: 0.827 AC: 34169 AN: 41308

American (AMR) AF: 0.560 AC: 8528 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1613 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2045 AN: 5126

South Asian (SAS) AF: 0.305 AC: 1463 AN: 4800

European-Finnish (FIN) AF: 0.391 AC: 4126 AN: 10540

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29880 AN: 67890

Other (OTH) AF: 0.544 AC: 1145 AN: 2106

Alfa AF: 0.505 Hom.: 7174

Bravo AF: 0.579

Asia WGS AF: 0.359 AC: 1249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.75
DANN	Benign	0.72
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0040
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: rs1701946; hg19: chr19-51503524; COSMIC: COSV51593960; COSMIC: COSV51593960;