Genetic Variant AHNAK2:p.Ala4325Val (chr14-104942477-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_138420.4(AHNAK2):c.12974C>T(p.Ala4325Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,612,262 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0021 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036826432).

BP6

Variant 14-104942477-G-A is Benign according to our data. Variant chr14-104942477-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2644639.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4 link	c.12974C>T	p.Ala4325Val	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2	Q8IVF2-1
AHNAK2	NM_001350929.2 link	c.12674C>T	p.Ala4225Val	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2 link	c.12674C>T	p.Ala4225Val	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1 link	c.12674C>T	p.Ala4225Val	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.12974C>T	p.Ala4325Val	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4	Q8IVF2-1
AHNAK2	ENST00000557457.1 link	c.-220-1499C>T		intron_variant	Intron 1 of 2	1		ENSP00000450998.1	Q8IVF2-2
AHNAK2	ENST00000555122.1 link	n.13102C>T		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

319

AN:

150758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00745

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000463

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00329

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.000603

AC:

150

AN:

248922

Hom.:

AF XY:

0.000422

AC XY:

AN XY:

135046

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000256

AC:

374

AN:

1461384

Hom.:

Cov.:

154

AF XY:

0.000204

AC XY:

148

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00726

Gnomad4 AMR exome

AF:

0.000649

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00212

AC:

320

AN:

150878

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

154

AN XY:

73732

show subpopulations

Gnomad4 AFR

AF:

0.00745

Gnomad4 AMR

AF:

0.000462

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.00242

ESP6500AA

AF:

0.00714

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000778

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AHNAK2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.052

DANN

Benign

0.41

DEOGEN2

Benign

0.019

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.0

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.43

REVEL

Benign

0.029

Sift

Benign

0.28

Sift4G

Benign

0.34

Polyphen

0.55

Vest4

0.055

MVP

0.030

ClinPred

0.018

GERP RS

-3.7

Varity_R

0.016

gMVP

0.0044

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over