Variant 14-104938860-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138420.4(AHNAK2):c.16591C>G(p.Gln5531Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,610 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 1 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13758668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AHNAK2	NM_138420.4 linkuse as main transcript	c.16591C>G	p.Gln5531Glu	missense_variant	7/7	ENST00000333244.6
AHNAK2	NM_001350929.2 linkuse as main transcript	c.16291C>G	p.Gln5431Glu	missense_variant	7/7
AHNAK2	XM_024449463.2 linkuse as main transcript	c.16291C>G	p.Gln5431Glu	missense_variant	7/7
AHNAK2	XM_047430904.1 linkuse as main transcript	c.16291C>G	p.Gln5431Glu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHNAK2	ENST00000333244.6 linkuse as main transcript	c.16591C>G	p.Gln5531Glu	missense_variant	7/7	5	NM_138420.4	P1	Q8IVF2-1
AHNAK2	ENST00000557457.1 linkuse as main transcript	c.1585C>G	p.Gln529Glu	missense_variant	3/3	1			Q8IVF2-2
AHNAK2	ENST00000555122.1 linkuse as main transcript	n.16719C>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248754

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135122

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000205

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.16591C>G (p.Q5531E) alteration is located in exon 7 (coding exon 7) of the AHNAK2 gene. This alteration results from a C to G substitution at nucleotide position 16591, causing the glutamine (Q) at amino acid position 5531 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.55

CADD

Benign

3.3

DANN

Benign

0.93

DEOGEN2

Benign

0.025

.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.10

Sift

Benign

0.34

T;D

Sift4G

Benign

0.32

T;T

Polyphen

0.99

.;D

Vest4

0.080

MutPred

0.33

.;Gain of catalytic residue at V5534 (P = 0.0061);

MVP

0.040

ClinPred

0.52

GERP RS

4.4

Varity_R

0.19

gMVP

0.0064

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over