Genetic Variant GKN1:c.463+3G>A (chr2-68980063-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_019617.4(GKN1):c.463+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,611,882 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 16 hom. )

Consequence

GKN1
NM_019617.4 splice_region, intron

Scores

Splicing: ADA: 0.00004195

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.209

Variant links:

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]

GKN1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 2-68980063-G-A is Benign according to our data. Variant chr2-68980063-G-A is described in ClinVar as [Benign]. Clinvar id is 712425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-68980063-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00609 (927/152316) while in subpopulation AFR AF= 0.0209 (870/41562). AF 95% confidence interval is 0.0198. There are 12 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GKN1	NM_019617.4 link	c.463+3G>A		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000377938.4	NP_062563.4	Q9NS71Q53YU7A0A8I5KHR1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GKN1	ENST00000377938.4 link	c.463+3G>A		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_019617.4	ENSP00000367172.3		Q9NS71Q53YU7
GKN1	ENST00000673932.3 link	c.505+3G>A		splice_region_variant, intron_variant	Intron 5 of 5			ENSP00000501093.2		A0A8I5KHR1

Frequencies

GnomAD3 genomes

AF:

0.00604

AC:

920

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00180

AC:

452

AN:

251426

Hom.:

AF XY:

0.00134

AC XY:

182

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0227

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000792

AC:

1156

AN:

1459566

Hom.:

Cov.:

AF XY:

0.000695

AC XY:

505

AN XY:

726238

show subpopulations

Gnomad4 AFR exome

AF:

0.0239

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00609

AC:

927

AN:

152316

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

447

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0209

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00355

Hom.:

Bravo

AF:

0.00707

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000042

dbscSNV1_RF

Benign

0.048

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over