chr14-104946366-C-G

Variant names:

• chr14-104946366-C-G
• rs192951700
• NM_138420.4:c.9085G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138420.4(AHNAK2):​c.9085G>C​(p.Glu3029Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,607,540 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.23
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035173297).
• BP6: Variant 14-104946366-C-G is Benign according to our data. Variant chr14-104946366-C-G is described in ClinVar as Benign. ClinVar VariationId is 402350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

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.9085G>C	p.Glu3029Gln	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.8785G>C	p.Glu2929Gln	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.9085G>C	p.Glu3029Gln	missense	Exon 7 of 7	ENSP00000353114.4
	AHNAK2	ENST00000557457.1	TSL:1	c.-220-5388G>C		intron	N/A	ENSP00000450998.1
	AHNAK2	ENST00000555122.1	TSL:5	n.9213G>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 509 AN: 147860 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000698

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00148

Gnomad ASJ AF: 0.00295

Gnomad EAS AF: 0.0621

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000181

Gnomad OTH AF: 0.00401

GnomAD2 exomes AF: 0.00632 AC: 1554 AN: 245912 AF XY: 0.00623

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.0552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000983

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00229 AC: 3343 AN: 1459536 Hom.: 112 Cov.: 175 AF XY: 0.00260 AC XY: 1887 AN XY: 725990

African (AFR) AF: 0.000389 AC: 13 AN: 33394

American (AMR) AF: 0.000876 AC: 39 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26048

East Asian (EAS) AF: 0.0311 AC: 1235 AN: 39690

South Asian (SAS) AF: 0.0161 AC: 1388 AN: 85974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5758

European-Non Finnish (NFE) AF: 0.0000873 AC: 97 AN: 1110692

Other (OTH) AF: 0.00835 AC: 503 AN: 60256

GnomAD4 genome AF: 0.00346 AC: 512 AN: 148004 Hom.: 22 Cov.: 32 AF XY: 0.00411 AC XY: 298 AN XY: 72458

African (AFR) AF: 0.000696 AC: 28 AN: 40214

American (AMR) AF: 0.00148 AC: 22 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 10 AN: 3392

East Asian (EAS) AF: 0.0619 AC: 299 AN: 4832

South Asian (SAS) AF: 0.0281 AC: 129 AN: 4598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000181 AC: 12 AN: 66404

Other (OTH) AF: 0.00595 AC: 12 AN: 2018

Alfa AF: 0.00141 Hom.: 4

ExAC AF: 0.00618 AC: 747

Asia WGS AF: 0.0510 AC: 179 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0030
DANN	Benign	0.11
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.83	N
PhyloP100		-4.2
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.022
Sift	Benign	0.67	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.014
ClinPred		0.00089	T
GERP RS		-0.25
Varity_R		0.023
gMVP		0.0086
Mutation Taster		=100/0	polymorphism (auto)

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: rs192951700; hg19: chr14-105412703; COSMIC: COSV60929580;