14-104938607-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138420.4(AHNAK2):c.16844C>T(p.Pro5615Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,612,960 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: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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]

ACMG classification

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=0.005892843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHNAK2	NM_138420.4	c.16844C>T	p.Pro5615Leu	missense_variant	7/7	ENST00000333244.6
AHNAK2	NM_001350929.2	c.16544C>T	p.Pro5515Leu	missense_variant	7/7
AHNAK2	XM_024449463.2	c.16544C>T	p.Pro5515Leu	missense_variant	7/7
AHNAK2	XM_047430904.1	c.16544C>T	p.Pro5515Leu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHNAK2	ENST00000333244.6	c.16844C>T	p.Pro5615Leu	missense_variant	7/7	5	NM_138420.4	P1
AHNAK2	ENST00000557457.1	c.1838C>T	p.Pro613Leu	missense_variant	3/3	1
AHNAK2	ENST00000555122.1	n.16972C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000389 AC: 96 AN: 247072 Hom.: 0 AF XY: 0.000410 AC XY: 55 AN XY: 134198

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00261

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000307 AC: 448 AN: 1460684 Hom.: 0 Cov.: 73 AF XY: 0.000303 AC XY: 220 AN XY: 726558

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.000359

Gnomad4 ASJ exome AF: 0.00280

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000566

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74460

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000250 Hom.: 1

Bravo AF: 0.000699

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00103 AC: 4

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000323 AC: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.16844C>T (p.P5615L) 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 16844, causing the proline (P) at amino acid position 5615 to be replaced by a leucine (L). 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	0.093
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Benign	0.69
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.053
Sift	Benign	1.0	T;T
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.55	.;P
Vest4		0.14
MVP		0.16
ClinPred		0.042	T
GERP RS		1.1
Varity_R		0.031
gMVP		0.040

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

Other links and lift over

dbSNP: rs199650197; hg19: chr14-105404944;