chr14-104938648-G-T

Variant summary

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

The NM_138420.4(AHNAK2):​c.16803C>A​(p.Asp5601Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000014 ( 0 hom. )

Consequence

AHNAK2
NM_138420.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.159
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=0.045665115).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AHNAK2NM_138420.4 linkuse as main transcriptc.16803C>A p.Asp5601Glu missense_variant 7/7 ENST00000333244.6
AHNAK2NM_001350929.2 linkuse as main transcriptc.16503C>A p.Asp5501Glu missense_variant 7/7
AHNAK2XM_024449463.2 linkuse as main transcriptc.16503C>A p.Asp5501Glu missense_variant 7/7
AHNAK2XM_047430904.1 linkuse as main transcriptc.16503C>A p.Asp5501Glu missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AHNAK2ENST00000333244.6 linkuse as main transcriptc.16803C>A p.Asp5601Glu missense_variant 7/75 NM_138420.4 P1Q8IVF2-1
AHNAK2ENST00000557457.1 linkuse as main transcriptc.1797C>A p.Asp599Glu missense_variant 3/31 Q8IVF2-2
AHNAK2ENST00000555122.1 linkuse as main transcriptn.16931C>A non_coding_transcript_exon_variant 6/65

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000408
AC:
1
AN:
245360
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133274
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000561
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:
0.00000137
AC:
2
AN:
1460022
Hom.:
0
Cov.:
74
AF XY:
0.00000138
AC XY:
1
AN XY:
726076
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000827
AC:
1

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 GeneticsAug 30, 2021The c.16803C>A (p.D5601E) 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 16803, causing the aspartic acid (D) at amino acid position 5601 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
0.32
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.020
.;T
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.35
T;T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.1
.;L
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.045
Sift
Benign
0.70
T;T
Sift4G
Benign
0.50
T;T
Polyphen
0.49
.;P
Vest4
0.055
MutPred
0.24
.;Gain of sheet (P = 0.0266);
MVP
0.014
ClinPred
0.35
T
GERP RS
0.76
Varity_R
0.020
gMVP
0.0059

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: rs775813968; hg19: chr14-105404985; API