Genetic Variant AHNAK2:p.Lys2170Met (chr14-104948942-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_138420.4(AHNAK2):c.6509A>T(p.Lys2170Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 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. K2170R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000011 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000024 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.84

Publications

6 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.21786895).

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.6509A>T	p.Lys2170Met	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.6209A>T	p.Lys2070Met	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.6509A>T	p.Lys2170Met	missense	Exon 7 of 7	ENSP00000353114.4	Q8IVF2-1
AHNAK2	ENST00000557457.1	TSL:1	c.-221+4939A>T		intron	N/A	ENSP00000450998.1	Q8IVF2-2
AHNAK2	ENST00000555122.1	TSL:5	n.6637A>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.0000107

AC:

AN:

93190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000309

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000237

AC:

AN:

1179134

Hom.:

Cov.:

104

AF XY:

0.0000272

AC XY:

AN XY:

588122

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32150

American (AMR)

AF:

0.0000248

AC:

AN:

40256

Ashkenazi Jewish (ASJ)

AF:

0.0000490

AC:

AN:

20388

East Asian (EAS)

AF:

0.00

AC:

AN:

38694

South Asian (SAS)

AF:

0.00

AC:

AN:

72904

European-Finnish (FIN)

AF:

0.0000225

AC:

AN:

44364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4230

European-Non Finnish (NFE)

AF:

0.0000240

AC:

AN:

876762

Other (OTH)

AF:

0.0000607

AC:

AN:

49386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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

AF:

0.0000107

AC:

AN:

93190

Hom.:

Cov.:

AF XY:

0.0000219

AC XY:

AN XY:

45630

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

34922

American (AMR)

AF:

0.00

AC:

AN:

9598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1382

East Asian (EAS)

AF:

0.00

AC:

AN:

4468

South Asian (SAS)

AF:

0.00

AC:

AN:

2578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

122

European-Non Finnish (NFE)

AF:

0.0000309

AC:

AN:

32384

Other (OTH)

AF:

0.00

AC:

AN:

1166

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

Eigen

Benign

0.13

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.72

M_CAP

Benign

0.010

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

1.8

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.44

REVEL

Benign

0.11

Sift

Benign

0.091

Sift4G

Benign

0.066

Polyphen

1.0

Vest4

0.28

MutPred

0.28

Gain of catalytic residue at V2165 (P = 0)

MVP

0.16

ClinPred

0.46

GERP RS

4.0

Varity_R

0.052

gMVP

0.011

Mutation Taster

=90/10

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