14-104938733-G-T

Variant summary

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

The NM_138420.4(AHNAK2):c.16718C>A(p.Pro5573Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5573S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.69

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:

Genome browser will be placed here

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=0.15742347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AHNAK2	NM_138420.4 linkuse as main transcript	c.16718C>A	p.Pro5573Gln	missense_variant	7/7	ENST00000333244.6
AHNAK2	NM_001350929.2 linkuse as main transcript	c.16418C>A	p.Pro5473Gln	missense_variant	7/7
AHNAK2	XM_024449463.2 linkuse as main transcript	c.16418C>A	p.Pro5473Gln	missense_variant	7/7
AHNAK2	XM_047430904.1 linkuse as main transcript	c.16418C>A	p.Pro5473Gln	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHNAK2	ENST00000333244.6 linkuse as main transcript	c.16718C>A	p.Pro5573Gln	missense_variant	7/7	5	NM_138420.4	P1	Q8IVF2-1
AHNAK2	ENST00000557457.1 linkuse as main transcript	c.1712C>A	p.Pro571Gln	missense_variant	3/3	1			Q8IVF2-2
AHNAK2	ENST00000555122.1 linkuse as main transcript	n.16846C>A		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152138

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

248572

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

135004

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000533

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

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

Jan 26, 2022

The c.16718C>A (p.P5573Q) alteration is located in exon 7 (coding exon 7) of the AHNAK2 gene. This alteration results from a C to A substitution at nucleotide position 16718, causing the proline (P) at amino acid position 5573 to be replaced by a glutamine (Q). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.97

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Benign

0.16

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.20

MVP

0.18

ClinPred

0.66

GERP RS

5.3

Varity_R

0.29

gMVP

0.017

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