2-68980765-C-A

Variant names:

• chr2-68980765-C-A
• rs200701146
• NM_019617.4:c.500C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019617.4(GKN1):​c.500C>A​(p.Thr167Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GKN1 NM_019617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.65

Genes affected

GKN1 (HGNC:23217): (gastrokine 1) The protein encoded by this gene is found to be down-regulated in human gastric cancer tissue as compared to normal gastric mucosa. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03483793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GKN1	NM_019617.4	c.500C>A	p.Thr167Lys	missense_variant	Exon 6 of 6	ENST00000377938.4	NP_062563.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GKN1	ENST00000377938.4	c.500C>A	p.Thr167Lys	missense_variant	Exon 6 of 6	1	NM_019617.4	ENSP00000367172.3
GKN1	ENST00000673932.3	c.542C>A	p.Thr181Lys	missense_variant	Exon 6 of 6			ENSP00000501093.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445506 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 720476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542C>A (p.T181K) alteration is located in exon 6 (coding exon 6) of the GKN1 gene. This alteration results from a C to A substitution at nucleotide position 542, causing the threonine (T) at amino acid position 181 to be replaced by a lysine (K). 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	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0010
DANN	Benign	0.18
DEOGEN2	Benign	0.019	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.016
Sift	Benign	0.46	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.45		Gain of ubiquitination at T181 (P = 0.023);
MVP		0.22
MPC		0.21
ClinPred		0.040	T
GERP RS		-9.1
Varity_R		0.028
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs200701146; hg19: chr2-69207897;