Genetic Variant NM_138420.4:c.9650T>A (chr14-104945801-A-T) – 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.9650T>A(p.Leu3217His) 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. L3217P) has been classified as Benign.

Frequency

Genomes: not found (cov: 21)

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.281

Publications

19 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=0.051134795).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHNAK2	NM_138420.4	MANE Select	c.9650T>A	p.Leu3217His	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.9350T>A	p.Leu3117His	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.9650T>A	p.Leu3217His	missense	Exon 7 of 7	ENSP00000353114.4
AHNAK2	ENST00000557457.1	TSL:1	c.-220-4823T>A		intron	N/A	ENSP00000450998.1
AHNAK2	ENST00000555122.1	TSL:5	n.9778T>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000548

AC:

AN:

182330

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000163

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

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.000159

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.8

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.024

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.15

M_CAP

Benign

0.0019

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

PhyloP100

-0.28

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.19

REVEL

Benign

0.015

Sift

Benign

0.034

Sift4G

Benign

0.21

Polyphen

0.28

Vest4

0.20

MutPred

0.29

Gain of catalytic residue at A3220 (P = 0.0021)

MVP

0.085

ClinPred

0.064

GERP RS

2.6

Varity_R

0.043

gMVP

0.010

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over