14-104948892-T-C

Variant names:

• chr14-104948892-T-C
• rs10134675
• NM_138420.4:c.6559A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_138420.4(AHNAK2):​c.6559A>G​(p.Met2187Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 124,458 control chromosomes in the GnomAD database, including 10,069 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2187L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (10069 hom., cov: 24)
  • Exomes 𝑓: 0.48 (167827 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.85
• Publications: 15 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2324872E-5).
• BP6: Variant 14-104948892-T-C is Benign according to our data. Variant chr14-104948892-T-C is described in ClinVar as Benign. ClinVar VariationId is 402351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10069 AR gene

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.6559A>G	p.Met2187Val	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.6259A>G	p.Met2087Val	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.6559A>G	p.Met2187Val	missense	Exon 7 of 7	ENSP00000353114.4
	AHNAK2	ENST00000557457.1	TSL:1	c.-221+4989A>G		intron	N/A	ENSP00000450998.1
	AHNAK2	ENST00000555122.1	TSL:5	n.6687A>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.397 AC: 49389 AN: 124378 Hom.: 10071 Cov.: 24

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.393 AC: 84496 AN: 214968 AF XY: 0.411

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.0750

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.470

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.476 AC: 643919 AN: 1353670 Hom.: 167827 Cov.: 114 AF XY: 0.479 AC XY: 322195 AN XY: 672594

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.214 AC: 6250 AN: 29208

American (AMR) AF: 0.265 AC: 11012 AN: 41566

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 14688 AN: 24634

East Asian (EAS) AF: 0.0894 AC: 2596 AN: 29046

South Asian (SAS) AF: 0.475 AC: 37301 AN: 78584

European-Finnish (FIN) AF: 0.378 AC: 18890 AN: 49948

Middle Eastern (MID) AF: 0.575 AC: 2828 AN: 4918

European-Non Finnish (NFE) AF: 0.504 AC: 524256 AN: 1040256

Other (OTH) AF: 0.470 AC: 26098 AN: 55510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.397 AC: 49398 AN: 124458 Hom.: 10069 Cov.: 24 AF XY: 0.387 AC XY: 23305 AN XY: 60222

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.263 AC: 8188 AN: 31156

American (AMR) AF: 0.342 AC: 4342 AN: 12688

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 1814 AN: 3070

East Asian (EAS) AF: 0.169 AC: 593 AN: 3502

South Asian (SAS) AF: 0.436 AC: 1537 AN: 3526

European-Finnish (FIN) AF: 0.347 AC: 3150 AN: 9068

Middle Eastern (MID) AF: 0.596 AC: 155 AN: 260

European-Non Finnish (NFE) AF: 0.487 AC: 28617 AN: 58728

Other (OTH) AF: 0.416 AC: 701 AN: 1686

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.378 Hom.: 1683

ExAC AF: 0.407 AC: 49108

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	0.047
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.36
DEOGEN2	Benign	0.017	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00054	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-3.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.015
ClinPred		0.0051	T
GERP RS		-0.58
Varity_R		0.019
gMVP		0.0050
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: rs10134675; hg19: chr14-105415229; COSMIC: COSV60906961; COSMIC: COSV60906961;