Genetic Variant NM_138420.4:c.12974C>T (chr14-104942477-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4325E) has been classified as Uncertain significance.

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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AR Classification: LIMITED Submitted by: Illumina, Ambry Genetics

AHNAK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 2644639.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138420.4. 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
	AHNAK2	NM_138420.4	MANE Select	c.12974C>T	p.Ala4325Val	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.12674C>T	p.Ala4225Val	missense	Exon 7 of 7	NP_001337858.1	Q8IVF2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AHNAK2	ENST00000333244.6	TSL:5 MANE Select	c.12974C>T	p.Ala4325Val	missense	Exon 7 of 7	ENSP00000353114.4	Q8IVF2-1
AHNAK2	ENST00000557457.1	TSL:1	c.-220-1499C>T		intron	N/A	ENSP00000450998.1	Q8IVF2-2
AHNAK2	ENST00000555122.1	TSL:5	n.13102C>T		non_coding_transcript_exon	Exon 6 of 6

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

GnomAD2 exomes

AF:

0.000603

AC:

150

AN:

248922

AF XY:

0.000422

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 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

African (AFR)

AF:

0.00726

AC:

243

AN:

33472

American (AMR)

AF:

0.000649

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1111680

Other (OTH)

AF:

0.000712

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00212

AC:

320

AN:

150878

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

154

AN XY:

73732

show subpopulations

African (AFR)

AF:

0.00745

AC:

306

AN:

41076

American (AMR)

AF:

0.000462

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

4976

South Asian (SAS)

AF:

0.00

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67638

Other (OTH)

AF:

0.00144

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.052

(source)

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

PhyloP100

-3.8

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

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over