5-55033807-G-T

Variant names:

• chr5-55033807-G-T
• rs200562138
• NM_002104.3:c.676G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002104.3(GZMK):​c.676G>T​(p.Ala226Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,472 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A226T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GZMK NM_002104.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

Genes affected

GZMK (HGNC:4711): (granzyme K) This gene product is a member of a group of related serine proteases from the cytoplasmic granules of cytotoxic lymphocytes. Cytolytic T lymphocytes (CTL) and natural killer (NK) cells share the remarkable ability to recognize, bind, and lyse specific target cells. They are thought to protect their host by lysing cells bearing on their surface 'nonself' antigens, usually peptides or proteins resulting from infection by intracellular pathogens. The protein described here lacks consensus sequences for N-glycosylation present in other granzymes. [provided by RefSeq, Jul 2008]

ENSG00000240535 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002104.3. 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
	GZMK	NM_002104.3	MANE Select	c.676G>T	p.Ala226Ser	missense	Exon 5 of 5	NP_002095.1	P49863

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GZMK	ENST00000231009.3	TSL:1 MANE Select	c.676G>T	p.Ala226Ser	missense	Exon 5 of 5	ENSP00000231009.2	P49863
	ENSG00000240535	ENST00000595218.5	TSL:5	n.464C>A		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000240535	ENST00000609699.5	TSL:5	n.1094C>A		non_coding_transcript_exon	Exon 7 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461472 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727046

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111806

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.49	N
PhyloP100		7.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		0.49	P
Vest4		0.44
MutPred		0.66		Gain of ubiquitination at K221 (P = 0.1008)
MVP		0.88
MPC		0.27
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.58
gMVP		0.68
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs200562138; hg19: chr5-54329635; COSMIC: COSV50246543; COSMIC: COSV50246543;