NM_001369775.2:c.-23+1G>A

Variant names:

• chr19-51082721-C-T
• rs117229324
• NM_001369775.2:c.-23+1G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001369775.2(KLK14):​c.-23+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,948 control chromosomes in the GnomAD database, including 255 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (7 hom., cov: 30)
  • Exomes 𝑓: 0.016 (248 hom.)
• Consequence: KLK14 NM_001369775.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0260
• Publications: 8 publications found

Genes affected

KLK14 (HGNC:6362): (kallikrein related peptidase 14) This gene encodes a member of the kallikrein subfamily of serine proteases that have diverse physiological functions such as regulation of blood pressure and desquamation. The altered expression of this gene is implicated in the progression of different cancers including breast and prostate tumors. The encoded protein is a precursor that is proteolytically processed to generate the functional enzyme. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-51082721-C-T is Benign according to our data. Variant chr19-51082721-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 808632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00965 (1469/152160) while in subpopulation SAS AF = 0.0328 (158/4816). AF 95% confidence interval is 0.0286. There are 7 homozygotes in GnomAd4. There are 738 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369775.2. 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
	KLK14	NM_001369775.2	MANE Select	c.-23+1G>A		splice_donor intron	N/A	NP_001356704.1	A0A1R3UHJ7
	KLK14	NM_001311182.2		c.-23+1G>A		splice_donor intron	N/A	NP_001298111.2	A0A1R3UHJ7
	KLK14	NM_022046.6		c.-23+1G>A		splice_donor intron	N/A	NP_071329.3	A0A1R3UHJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK14	ENST00000650543.2	MANE Select	c.-23+1G>A		splice_donor intron	N/A	ENSP00000497141.1	A0A1R3UHJ7
	KLK14	ENST00000156499.7	TSL:1	c.-23+1G>A		splice_donor intron	N/A	ENSP00000156499.3	A0A1R3UHJ7
	KLK14	ENST00000391802.1	TSL:5	c.26+1G>A		splice_donor intron	N/A	ENSP00000375678.1	Q9P0G3

Frequencies

GnomAD3 genomes AF: 0.00966 AC: 1468 AN: 152042 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.0135 AC: 3368 AN: 249204 AF XY: 0.0149

Gnomad AFR exome AF: 0.00278

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00798

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0155 AC: 22661 AN: 1461788 Hom.: 248 Cov.: 31 AF XY: 0.0162 AC XY: 11815 AN XY: 727194

African (AFR) AF: 0.00206 AC: 69 AN: 33478

American (AMR) AF: 0.00566 AC: 253 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0349 AC: 3013 AN: 86246

European-Finnish (FIN) AF: 0.00813 AC: 434 AN: 53408

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5742

European-Non Finnish (NFE) AF: 0.0163 AC: 18088 AN: 1111966

Other (OTH) AF: 0.0114 AC: 690 AN: 60392

GnomAD4 genome AF: 0.00965 AC: 1469 AN: 152160 Hom.: 7 Cov.: 30 AF XY: 0.00992 AC XY: 738 AN XY: 74404

African (AFR) AF: 0.00236 AC: 98 AN: 41510

American (AMR) AF: 0.00504 AC: 77 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.0328 AC: 158 AN: 4816

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0152 AC: 1032 AN: 67996

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.0143 Hom.: 60

Bravo AF: 0.00872

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00250 AC: 10

ESP6500EA AF: 0.0147 AC: 123

ExAC AF: 0.0148 AC: 1794

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0165

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.74
Eigen	Benign	0.10
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.030	N
PhyloP100		-0.026
GERP RS		-0.95
PromoterAI		-0.069	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 1

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

Other links and lift over

dbSNP: rs117229324; hg19: chr19-51585978; COSMIC: COSV99030603;