dbSNP rs537379922: AHNAK2:p.Gly1967Ala (chr14-104949551-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138420.4(AHNAK2):c.5900G>C(p.Gly1967Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,588,242 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00022 ( 2 hom., cov: 30)

Exomes 𝑓: 0.000030 ( 5 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.69

Variant links:

Genes affected

AHNAK2 (HGNC:20125): (AHNAK nucleoprotein 2) This gene encodes a large nucleoprotein. The encoded protein has a tripartite domain structure with a relatively short N-terminus and a long C-terminus, separated by a large body of repeats. The N-terminal PSD-95/Discs-large/ZO-1 (PDZ)-like domain is thought to function in the formation of stable homodimers. The encoded protein may play a role in calcium signaling by associating with calcium channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

AHNAK2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016241997).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4 link	c.5900G>C	p.Gly1967Ala	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2	Q8IVF2-1
AHNAK2	NM_001350929.2 link	c.5600G>C	p.Gly1867Ala	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2 link	c.5600G>C	p.Gly1867Ala	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1 link	c.5600G>C	p.Gly1867Ala	missense_variant	Exon 7 of 7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AHNAK2	ENST00000333244.6 link	c.5900G>C	p.Gly1967Ala	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4	Q8IVF2-1
AHNAK2	ENST00000557457.1 link	c.-221+4330G>C		intron_variant	Intron 1 of 2	1		ENSP00000450998.1	Q8IVF2-2
AHNAK2	ENST00000555122.1 link	n.6028G>C		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.000225

AC:

AN:

146842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000611

AC:

AN:

245338

Hom.:

AF XY:

0.0000675

AC XY:

AN XY:

133272

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000990

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000298

AC:

AN:

1441288

Hom.:

Cov.:

168

AF XY:

0.0000362

AC XY:

AN XY:

717276

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.000163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000820

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000912

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000225

AC:

AN:

146954

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

71578

show subpopulations

Gnomad4 AFR

AF:

0.000325

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

ExAC

AF:

0.0000499

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.11

DANN

Benign

0.77

DEOGEN2

Benign

0.022

Eigen

Benign

-0.85

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.40

M_CAP

Benign

0.0020

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.1

REVEL

Benign

0.032

Sift

Benign

0.82

Sift4G

Benign

0.23

Polyphen

0.11

Vest4

0.14

MutPred

0.19

Gain of catalytic residue at G1972 (P = 0.0962);

MVP

0.030

ClinPred

0.021

GERP RS

0.61

Varity_R

0.025

gMVP

0.017

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over