Genetic Variant AHNAK2:p.Asp1425Ala (chr14-104951177-T-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000333244.6(AHNAK2):c.4274A>C(p.Asp1425Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,071,286 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1425G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 6 hom., cov: 18)

Exomes 𝑓: 0.000049 ( 9 hom. )

Consequence

AHNAK2
ENST00000333244.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.791

Publications

0 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037620366).

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000333244.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHNAK2	NM_138420.4	MANE Select	c.4274A>C	p.Asp1425Ala	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.3974A>C	p.Asp1325Ala	missense	Exon 7 of 7	NP_001337858.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHNAK2	ENST00000333244.6	TSL:5 MANE Select	c.4274A>C	p.Asp1425Ala	missense	Exon 7 of 7	ENSP00000353114.4
AHNAK2	ENST00000557457.1	TSL:1	c.-221+2704A>C		intron	N/A	ENSP00000450998.1
AHNAK2	ENST00000555122.1	TSL:5	n.4402A>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

107024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000924

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000551

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

GnomAD2 exomes

AF:

0.000208

AC:

AN:

178006

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.000783

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000487

AC:

AN:

964140

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

478740

show subpopulations

African (AFR)

AF:

0.000503

AC:

AN:

31808

American (AMR)

AF:

0.000688

AC:

AN:

36346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14148

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38962

South Asian (SAS)

AF:

0.0000334

AC:

AN:

59834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3504

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

699310

Other (OTH)

AF:

0.0000720

AC:

AN:

41678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

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:

0.000373

AC:

AN:

107146

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

AN XY:

52408

show subpopulations

African (AFR)

AF:

0.000921

AC:

AN:

36898

American (AMR)

AF:

0.000550

AC:

AN:

10900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1662

East Asian (EAS)

AF:

0.00

AC:

AN:

4764

South Asian (SAS)

AF:

0.00

AC:

AN:

3054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

40768

Other (OTH)

AF:

0.00

AC:

AN:

1400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.000287

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000164

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.54

M_CAP

Benign

0.0077

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

PhyloP100

0.79

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.080

Sift

Benign

0.095

Sift4G

Benign

0.32

Polyphen

0.94

Vest4

0.19

MVP

0.18

ClinPred

0.076

GERP RS

1.8

Varity_R

0.089

gMVP

0.017

Mutation Taster

=97/3

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

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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