14-104945801-A-T

Position:

• chr14-104945801-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138420.4(AHNAK2):​c.9650T>A​(p.Leu3217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051134795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.9650T>A	p.Leu3217His	missense_variant	7/7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.9350T>A	p.Leu3117His	missense_variant	7/7		NP_001337858.1
AHNAK2	XM_024449463.2	c.9350T>A	p.Leu3117His	missense_variant	7/7		XP_024305231.1
AHNAK2	XM_047430904.1	c.9350T>A	p.Leu3117His	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>A	p.Leu3217His	missense_variant	7/7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-220-4823T>A		intron_variant		1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.9778T>A		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 99194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000163

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 21

ExAC AF: 0.000159 AC: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.8
DANN	Benign	0.28
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.015
Sift	Benign	0.034	D
Sift4G	Benign	0.21	T
Polyphen		0.28	B
Vest4		0.20
MutPred		0.29		Gain of catalytic residue at A3220 (P = 0.0021);
MVP		0.085
ClinPred		0.064	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;