dbSNP rs28714612: AHNAK2:p.Met3260Arg (chr14-104945672-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138420.4(AHNAK2):c.9779T>G(p.Met3260Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. M3260T) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.49

Publications

16 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036340028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4 link	c.9779T>G	p.Met3260Arg	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2	Q8IVF2-1
AHNAK2	NM_001350929.2 link	c.9479T>G	p.Met3160Arg	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2 link	c.9479T>G	p.Met3160Arg	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1 link	c.9479T>G	p.Met3160Arg	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.9779T>G	p.Met3260Arg	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4	Q8IVF2-1
AHNAK2	ENST00000557457.1 link	c.-220-4694T>G		intron_variant	Intron 1 of 2	1		ENSP00000450998.1	Q8IVF2-2
AHNAK2	ENST00000555122.1 link	n.9907T>G		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000514

AC:

AN:

194730

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000108

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.08e-7

AC:

AN:

1411730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31410

American (AMR)

AF:

0.00

AC:

AN:

42402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25134

East Asian (EAS)

AF:

0.00

AC:

AN:

38560

South Asian (SAS)

AF:

0.00

AC:

AN:

82258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5174

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077592

Other (OTH)

AF:

0.00

AC:

AN:

58224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

1628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0060

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.031

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.49

M_CAP

Benign

0.00084

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.34

PhyloP100

-2.5

PrimateAI

Benign

0.18

PROVEAN

Benign

-2.0

REVEL

Benign

0.070

Sift

Benign

0.22

Sift4G

Benign

0.092

Polyphen

0.011

Vest4

0.14

MutPred

0.25

Gain of catalytic residue at L3255 (P = 0.016);

MVP

0.014

ClinPred

0.053

GERP RS

-4.7

Varity_R

0.18

gMVP

0.026

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over