14-104948942-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_138420.4(AHNAK2):c.6509A>G(p.Lys2170Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (173 hom., cov: 19)
  • Exomes 𝑓: 0.12 (49964 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016698241).
• BP6: Variant 14-104948942-T-C is Benign according to our data. Variant chr14-104948942-T-C is described in ClinVar as [Benign]. Clinvar id is 402352.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5916 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHNAK2	NM_138420.4	c.6509A>G	p.Lys2170Arg	missense_variant	7/7	ENST00000333244.6
AHNAK2	NM_001350929.2	c.6209A>G	p.Lys2070Arg	missense_variant	7/7
AHNAK2	XM_024449463.2	c.6209A>G	p.Lys2070Arg	missense_variant	7/7
AHNAK2	XM_047430904.1	c.6209A>G	p.Lys2070Arg	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHNAK2	ENST00000333244.6	c.6509A>G	p.Lys2170Arg	missense_variant	7/7	5	NM_138420.4	P1
AHNAK2	ENST00000557457.1	c.-221+4939A>G		intron_variant		1
AHNAK2	ENST00000555122.1	n.6637A>G		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3784 AN: 86654 Hom.: 174 Cov.: 19 FAILED QC

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.0444

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0498

GnomAD3 exomes AF: 0.0966 AC: 19334 AN: 200092 Hom.: 5916 AF XY: 0.104 AC XY: 11307 AN XY: 109056

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.00577

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.155

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.120 AC: 130577 AN: 1090618 Hom.: 49964 Cov.: 104 AF XY: 0.124 AC XY: 67073 AN XY: 542508

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.0610

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.00334

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.0828

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0436 AC: 3786 AN: 86786 Hom.: 173 Cov.: 19 AF XY: 0.0431 AC XY: 1841 AN XY: 42704

Gnomad4 AFR AF: 0.0440

Gnomad4 AMR AF: 0.0387

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.00526

Gnomad4 SAS AF: 0.0445

Gnomad4 FIN AF: 0.0489

Gnomad4 NFE AF: 0.0482

Gnomad4 OTH AF: 0.0480

Alfa AF: 0.353 Hom.: 3610

ExAC AF: 0.121 AC: 14301

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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.080
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.13
Sift	Benign	0.78	T
Sift4G	Benign	0.68	T
Polyphen		0.99	D
Vest4		0.066
ClinPred		0.018	T
GERP RS		4.0
Varity_R		0.028
gMVP		0.0033

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: rs201127689; hg19: chr14-105415279; COSMIC: COSV60910083; COSMIC: COSV60910083;