chr14-104938773-C-T

Variant summary

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

The NM_138420.4(AHNAK2):​c.16678G>A​(p.Asp5560Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36
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]

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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=0.043355137).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AHNAK2NM_138420.4 linkuse as main transcriptc.16678G>A p.Asp5560Asn missense_variant 7/7 ENST00000333244.6
AHNAK2NM_001350929.2 linkuse as main transcriptc.16378G>A p.Asp5460Asn missense_variant 7/7
AHNAK2XM_024449463.2 linkuse as main transcriptc.16378G>A p.Asp5460Asn missense_variant 7/7
AHNAK2XM_047430904.1 linkuse as main transcriptc.16378G>A p.Asp5460Asn missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AHNAK2ENST00000333244.6 linkuse as main transcriptc.16678G>A p.Asp5560Asn missense_variant 7/75 NM_138420.4 P1Q8IVF2-1
AHNAK2ENST00000557457.1 linkuse as main transcriptc.1672G>A p.Asp558Asn missense_variant 3/31 Q8IVF2-2
AHNAK2ENST00000555122.1 linkuse as main transcriptn.16806G>A non_coding_transcript_exon_variant 6/65

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152220
Hom.:
0
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:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000723
AC:
18
AN:
248952
Hom.:
0
AF XY:
0.0000888
AC XY:
12
AN XY:
135152
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000588
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461624
Hom.:
0
Cov.:
73
AF XY:
0.0000371
AC XY:
27
AN XY:
727084
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000522
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.0000268
AC XY:
2
AN XY:
74492
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:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000745
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 GeneticsMar 07, 2024The c.16678G>A (p.D5560N) alteration is located in exon 7 (coding exon 7) of the AHNAK2 gene. This alteration results from a G to A substitution at nucleotide position 16678, causing the aspartic acid (D) at amino acid position 5560 to be replaced by an asparagine (N). 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
0.15
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
10
DANN
Uncertain
0.99
DEOGEN2
Benign
0.023
.;T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.47
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.043
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.6
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-2.5
N;N
REVEL
Benign
0.077
Sift
Benign
0.69
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.99
.;D
Vest4
0.14
MutPred
0.19
.;Gain of catalytic residue at V5559 (P = 0.025);
MVP
0.048
ClinPred
0.26
T
GERP RS
3.6
Varity_R
0.052
gMVP
0.010

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: rs541261629; hg19: chr14-105405110; API