rs200384326

Variant names:

• chr14-104945801-A-C
• rs200384326
• NM_138420.4:c.9650T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-104945801-A-C
• chr14-104945801-A-G
• chr14-104945801-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138420.4(AHNAK2):​c.9650T>G​(p.Leu3217Arg) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3217P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.281
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: LIMITED Submitted by: Illumina, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049329102).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138420.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHNAK2	NM_138420.4	MANE Select	c.9650T>G	p.Leu3217Arg	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.9350T>G	p.Leu3117Arg	missense	Exon 7 of 7	NP_001337858.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHNAK2	ENST00000333244.6	TSL:5 MANE Select	c.9650T>G	p.Leu3217Arg	missense	Exon 7 of 7	ENSP00000353114.4
	AHNAK2	ENST00000557457.1	TSL:1	c.-220-4823T>G		intron	N/A	ENSP00000450998.1
	AHNAK2	ENST00000555122.1	TSL:5	n.9778T>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 21

ExAC AF: 0.000100 AC: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.1
DANN	Benign	0.42
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.28
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.019
Sift	Benign	0.054	T
Sift4G	Benign	0.69	T
Polyphen		0.024	B
Vest4		0.17
MutPred		0.34		Gain of catalytic residue at A3220 (P = 0.0055)
MVP		0.061
ClinPred		0.064	T
GERP RS		2.6
Varity_R		0.053
gMVP		0.0064
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200384326; hg19: chr14-105412138;