14-104945801-A-G

Position:

• chr14-104945801-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_138420.4(AHNAK2):​c.9650T>C​(p.Leu3217Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.10 (668 hom., cov: 21)
  • Exomes 𝑓: 0.32 (142817 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.281

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004053861).
• BP6: Variant 14-104945801-A-G is Benign according to our data. Variant chr14-104945801-A-G is described in ClinVar as [Benign]. Clinvar id is 402349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.9650T>C	p.Leu3217Pro	missense_variant	7/7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.9350T>C	p.Leu3117Pro	missense_variant	7/7		NP_001337858.1
AHNAK2	XM_024449463.2	c.9350T>C	p.Leu3117Pro	missense_variant	7/7		XP_024305231.1
AHNAK2	XM_047430904.1	c.9350T>C	p.Leu3117Pro	missense_variant	7/7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHNAK2	ENST00000333244.6	c.9650T>C	p.Leu3217Pro	missense_variant	7/7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-220-4823T>C		intron_variant		1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.9778T>C		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8316 AN: 82918 Hom.: 669 Cov.: 21 FAILED QC

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0949

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.162 AC: 29520 AN: 182330 Hom.: 9705 AF XY: 0.165 AC XY: 16388 AN XY: 99194

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.0448

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.0963

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.227

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.315 AC: 303377 AN: 962178 Hom.: 142817 Cov.: 82 AF XY: 0.320 AC XY: 151741 AN XY: 474576

Gnomad4 AFR exome AF: 0.0676

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.100 AC: 8312 AN: 83024 Hom.: 668 Cov.: 21 AF XY: 0.0938 AC XY: 3829 AN XY: 40828

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.0936

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0949

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.123

Alfa AF: 0.324 Hom.: 2467

ExAC AF: 0.194 AC: 23139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2018	This variant is associated with the following publications: (PMID: 23042115) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	0.045
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.13
DANN	Benign	0.30
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00065	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.041
Sift	Benign	0.11	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.055
ClinPred		0.0026	T
GERP RS		2.6
Varity_R		0.043
gMVP		0.010

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: rs200384326; hg19: chr14-105412138; COSMIC: COSV60906872;