14-104948892-T-C

Variant names:

• chr14-104948892-T-C
• rs10134675
• NM_138420.4:c.6559A>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.6559A>G​(p.Met2187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 124,458 control chromosomes in the GnomAD database, including 10,069 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 0.40 (10069 hom., cov: 24)
  • Exomes 𝑓: 0.48 (167827 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.85

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2324872E-5).
• BP6: Variant 14-104948892-T-C is Benign according to our data. Variant chr14-104948892-T-C is described in ClinVar as [Benign]. Clinvar id is 402351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.6559A>G	p.Met2187Val	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.6259A>G	p.Met2087Val	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2	c.6259A>G	p.Met2087Val	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1	c.6259A>G	p.Met2087Val	missense_variant	Exon 7 of 7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHNAK2	ENST00000333244.6	c.6559A>G	p.Met2187Val	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-221+4989A>G		intron_variant	Intron 1 of 2	1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.6687A>G		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.397 AC: 49389 AN: 124378 Hom.: 10071 Cov.: 24

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.393 AC: 84496 AN: 214968 Hom.: 22539 AF XY: 0.411 AC XY: 47668 AN XY: 115920

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.0750

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.470

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.476 AC: 643919 AN: 1353670 Hom.: 167827 Cov.: 114 AF XY: 0.479 AC XY: 322195 AN XY: 672594

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.596

Gnomad4 EAS exome AF: 0.0894

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.397 AC: 49398 AN: 124458 Hom.: 10069 Cov.: 24 AF XY: 0.387 AC XY: 23305 AN XY: 60222

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.591

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.347

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.416

Alfa AF: 0.378 Hom.: 1683

ExAC AF: 0.407 AC: 49108

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.36
DEOGEN2	Benign	0.017	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00054	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.015
ClinPred		0.0051	T
GERP RS		-0.58
Varity_R		0.019
gMVP		0.0050

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: rs10134675; hg19: chr14-105415229; COSMIC: COSV60906961; COSMIC: COSV60906961;