19-50819253-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002257.4(KLK1):c.730G>T(p.Ala244Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A244V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLK1 NM_002257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

KLK1 (HGNC:6357): (kallikrein 1) 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 a cluster on chromosome 19. This protein is functionally conserved in its capacity to release the vasoactive peptide, Lys-bradykinin, from low molecular weight kininogen. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK1	NM_002257.4	c.730G>T	p.Ala244Ser	missense_variant	5/5	ENST00000301420.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK1	ENST00000301420.3	c.730G>T	p.Ala244Ser	missense_variant	5/5	1	NM_002257.4	P1
KLK1	ENST00000593859.5	n.887G>T		non_coding_transcript_exon_variant	4/4	2
KLK1	ENST00000593325.5	c.*1539G>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	2
KLK1	ENST00000596300.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.730G>T (p.A244S) alteration is located in exon 5 (coding exon 5) of the KLK1 gene. This alteration results from a G to T substitution at nucleotide position 730, causing the alanine (A) at amino acid position 244 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.24	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.083
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0060	B
Vest4		0.31
MutPred		0.74		Gain of glycosylation at A244 (P = 0.0321);
MVP		0.061
MPC		0.21
ClinPred		0.31	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.37
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -8

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51322509;