14-104945672-A-G

Position:

• chr14-104945672-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138420.4(AHNAK2):​c.9779T>C​(p.Met3260Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 930,696 control chromosomes in the GnomAD database, including 163,512 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 0.22 (3186 hom., cov: 23)
  • Exomes 𝑓: 0.44 (163512 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.49

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7645955E-4).
• BP6: Variant 14-104945672-A-G is Benign according to our data. Variant chr14-104945672-A-G is described in ClinVar as [Benign]. Clinvar id is 402348.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHNAK2	NM_138420.4	c.9779T>C	p.Met3260Thr	missense_variant	7/7	ENST00000333244.6
AHNAK2	NM_001350929.2	c.9479T>C	p.Met3160Thr	missense_variant	7/7
AHNAK2	XM_024449463.2	c.9479T>C	p.Met3160Thr	missense_variant	7/7
AHNAK2	XM_047430904.1	c.9479T>C	p.Met3160Thr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHNAK2	ENST00000333244.6	c.9779T>C	p.Met3260Thr	missense_variant	7/7	5	NM_138420.4	P1
AHNAK2	ENST00000557457.1	c.-220-4694T>C		intron_variant		1
AHNAK2	ENST00000555122.1	n.9907T>C		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 21302 AN: 95688 Hom.: 3185 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.0455

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.433 AC: 84294 AN: 194730 Hom.: 21512 AF XY: 0.448 AC XY: 47873 AN XY: 106742

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.139

Gnomad SAS exome AF: 0.482

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.506

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.444 AC: 412960 AN: 930696 Hom.: 163512 Cov.: 83 AF XY: 0.447 AC XY: 207998 AN XY: 465182

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.642

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.488

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.222 AC: 21306 AN: 95772 Hom.: 3186 Cov.: 23 AF XY: 0.220 AC XY: 10468 AN XY: 47496

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.0451

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.232

Alfa AF: 0.326 Hom.: 1628

ExAC AF: 0.443 AC: 53200

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0020
DANN	Benign	0.20
DEOGEN2	Benign	0.017	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.76	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.044
Sift	Benign	0.32	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.039
ClinPred		0.012	T
GERP RS		-4.7
Varity_R		0.038
gMVP		0.012

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: rs28714612; hg19: chr14-105412009; COSMIC: COSV60906939;