rs192951700

Positions:

• chr14-104946366-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138420.4(AHNAK2):​c.9085G>C​(p.Glu3029Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,607,540 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.23

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035173297).
• BP6: Variant 14-104946366-C-G is Benign according to our data. Variant chr14-104946366-C-G is described in ClinVar as [Benign]. Clinvar id is 402350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.9085G>C	p.Glu3029Gln	missense_variant	7/7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.8785G>C	p.Glu2929Gln	missense_variant	7/7		NP_001337858.1
AHNAK2	XM_024449463.2	c.8785G>C	p.Glu2929Gln	missense_variant	7/7		XP_024305231.1
AHNAK2	XM_047430904.1	c.8785G>C	p.Glu2929Gln	missense_variant	7/7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHNAK2	ENST00000333244.6	c.9085G>C	p.Glu3029Gln	missense_variant	7/7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-220-5388G>C		intron_variant		1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.9213G>C		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 509 AN: 147860 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000698

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00148

Gnomad ASJ AF: 0.00295

Gnomad EAS AF: 0.0621

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.00401

GnomAD3 exomes AF: 0.00632 AC: 1554 AN: 245912 Hom.: 54 AF XY: 0.00623 AC XY: 831 AN XY: 133346

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.0552

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000983

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00229 AC: 3343 AN: 1459536 Hom.: 112 Cov.: 175 AF XY: 0.00260 AC XY: 1887 AN XY: 725990

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000876

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0311

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000873

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.00346 AC: 512 AN: 148004 Hom.: 22 Cov.: 32 AF XY: 0.00411 AC XY: 298 AN XY: 72458

Gnomad4 AFR AF: 0.000696

Gnomad4 AMR AF: 0.00148

Gnomad4 ASJ AF: 0.00295

Gnomad4 EAS AF: 0.0619

Gnomad4 SAS AF: 0.0281

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000181

Gnomad4 OTH AF: 0.00595

Alfa AF: 0.00141 Hom.: 4

ExAC AF: 0.00618 AC: 747

Asia WGS AF: 0.0510 AC: 179 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0030
DANN	Benign	0.11
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.83	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.022
Sift	Benign	0.67	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.014
ClinPred		0.00089	T
GERP RS		-0.25
Varity_R		0.023
gMVP		0.0086

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: rs192951700; hg19: chr14-105412703; COSMIC: COSV60929580;