chr14-104938734-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138420.4(AHNAK2):​c.16717C>T​(p.Pro5573Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. P5573Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.021800876).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AHNAK2NM_138420.4 linkuse as main transcriptc.16717C>T p.Pro5573Ser missense_variant 7/7 ENST00000333244.6
AHNAK2NM_001350929.2 linkuse as main transcriptc.16417C>T p.Pro5473Ser missense_variant 7/7
AHNAK2XM_024449463.2 linkuse as main transcriptc.16417C>T p.Pro5473Ser missense_variant 7/7
AHNAK2XM_047430904.1 linkuse as main transcriptc.16417C>T p.Pro5473Ser missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AHNAK2ENST00000333244.6 linkuse as main transcriptc.16717C>T p.Pro5573Ser missense_variant 7/75 NM_138420.4 P1Q8IVF2-1
AHNAK2ENST00000557457.1 linkuse as main transcriptc.1711C>T p.Pro571Ser missense_variant 3/31 Q8IVF2-2
AHNAK2ENST00000555122.1 linkuse as main transcriptn.16845C>T non_coding_transcript_exon_variant 6/65

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
1
Cov.:
32
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:
0.000963
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000113
AC:
28
AN:
248578
Hom.:
0
AF XY:
0.000104
AC XY:
14
AN XY:
135012
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00156
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:
0.0000267
AC:
39
AN:
1461536
Hom.:
0
Cov.:
73
AF XY:
0.0000344
AC XY:
25
AN XY:
727022
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000882
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
1
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000963
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000414
AC:
5

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 submitterclinical testingAmbry GeneticsOct 04, 2022The c.16717C>T (p.P5573S) alteration is located in exon 7 (coding exon 7) of the AHNAK2 gene. This alteration results from a C to T substitution at nucleotide position 16717, causing the proline (P) at amino acid position 5573 to be replaced by a serine (S). 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
0.28
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
.;T
Eigen
Benign
-0.044
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.27
N
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.022
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.25
T
PROVEAN
Pathogenic
-5.2
D;D
REVEL
Benign
0.16
Sift
Benign
0.030
D;D
Sift4G
Uncertain
0.023
D;D
Polyphen
0.95
.;P
Vest4
0.077
MutPred
0.39
.;Gain of catalytic residue at G5571 (P = 0.0157);
MVP
0.088
ClinPred
0.29
T
GERP RS
5.3
Varity_R
0.23
gMVP
0.019

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.

Other links and lift over

dbSNP: rs781525999; hg19: chr14-105405071; API