14-104948892-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_138420.4(AHNAK2):c.6559A>C(p.Met2187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,590,774 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. M2187V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.85

Publications

15 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=0.0052985847).

BP6

Variant 14-104948892-T-G is Benign according to our data. Variant chr14-104948892-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2672573.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHNAK2	NM_138420.4	MANE Select	c.6559A>C	p.Met2187Leu	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.6259A>C	p.Met2087Leu	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.6559A>C	p.Met2187Leu	missense	Exon 7 of 7	ENSP00000353114.4
AHNAK2	ENST00000557457.1	TSL:1	c.-221+4989A>C		intron	N/A	ENSP00000450998.1
AHNAK2	ENST00000555122.1	TSL:5	n.6687A>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

137330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000579

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000228

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000956

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000284

AC:

AN:

214968

AF XY:

0.000345

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000611

Gnomad FIN exome

AF:

0.0000532

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.000564

GnomAD4 exome

AF:

0.000129

AC:

187

AN:

1453340

Hom.:

Cov.:

114

AF XY:

0.000148

AC XY:

107

AN XY:

723012

show subpopulations

African (AFR)

AF:

0.000183

AC:

AN:

32726

American (AMR)

AF:

0.000837

AC:

AN:

44192

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26056

East Asian (EAS)

AF:

0.000317

AC:

AN:

37842

South Asian (SAS)

AF:

0.000480

AC:

AN:

85350

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52754

Middle Eastern (MID)

AF:

0.000367

AC:

AN:

5452

European-Non Finnish (NFE)

AF:

0.0000730

AC:

AN:

1109104

Other (OTH)

AF:

0.000100

AC:

AN:

59864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

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:

0.000196

AC:

AN:

137434

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

AN XY:

66582

show subpopulations

African (AFR)

AF:

0.000164

AC:

AN:

36656

American (AMR)

AF:

0.000578

AC:

AN:

13836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3216

East Asian (EAS)

AF:

0.000229

AC:

AN:

4370

South Asian (SAS)

AF:

0.00149

AC:

AN:

4020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.0000956

AC:

AN:

62782

Other (OTH)

AF:

0.00

AC:

AN:

1856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.0000575

Hom.:

1683

ExAC

AF:

0.000331

AC:

ClinVar

ClinVar submissions as Germline

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

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.11

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.017

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.27

M_CAP

Benign

0.0019

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.060

PhyloP100

-3.8

PrimateAI

Benign

0.25

PROVEAN

Benign

0.40

REVEL

Benign

0.012

Sift

Benign

0.34

Sift4G

Benign

0.30

Polyphen

0.074

Vest4

0.064

MutPred

0.27

Gain of catalytic residue at P2190 (P = 0.0261)

MVP

0.014

ClinPred

0.0018

GERP RS

-0.58

Varity_R

0.030

gMVP

0.0041

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over