14-104945672-A-G

Variant names:

• chr14-104945672-A-G
• rs28714612
• NM_138420.4:c.9779T>C

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.9779T>C​(p.Met3260Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 930,696 control chromosomes in the GnomAD database, including 163,512 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. M3260V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3186 hom., cov: 23)
  • Exomes 𝑓: 0.44 (163512 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.49
• Publications: 16 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=1.7645955E-4).
• BP6: Variant 14-104945672-A-G is Benign according to our data. Variant chr14-104945672-A-G is described in ClinVar as Benign. ClinVar VariationId is 402348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 163512 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.9779T>C	p.Met3260Thr	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.9479T>C	p.Met3160Thr	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2	c.9479T>C	p.Met3160Thr	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1	c.9479T>C	p.Met3160Thr	missense_variant	Exon 7 of 7		XP_047286860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHNAK2	ENST00000333244.6	c.9779T>C	p.Met3260Thr	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-220-4694T>C		intron_variant	Intron 1 of 2	1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.9907T>C		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.223 AC: 21302 AN: 95688 Hom.: 3185 Cov.: 23

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.0455

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.433 AC: 84294 AN: 194730 AF XY: 0.448

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.506

Gnomad OTH exome AF: 0.485

GnomAD4 exome AF: 0.444 AC: 412960 AN: 930696 Hom.: 163512 Cov.: 83 AF XY: 0.447 AC XY: 207998 AN XY: 465182

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

African (AFR) AF: 0.195 AC: 4326 AN: 22176

American (AMR) AF: 0.228 AC: 7619 AN: 33468

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 11119 AN: 17328

East Asian (EAS) AF: 0.0303 AC: 1022 AN: 33726

South Asian (SAS) AF: 0.415 AC: 24141 AN: 58128

European-Finnish (FIN) AF: 0.296 AC: 10296 AN: 34832

Middle Eastern (MID) AF: 0.560 AC: 2039 AN: 3638

European-Non Finnish (NFE) AF: 0.488 AC: 335926 AN: 688948

Other (OTH) AF: 0.428 AC: 16472 AN: 38452

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.222 AC: 21306 AN: 95772 Hom.: 3186 Cov.: 23 AF XY: 0.220 AC XY: 10468 AN XY: 47496

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

African (AFR) AF: 0.136 AC: 4090 AN: 30104

American (AMR) AF: 0.205 AC: 2189 AN: 10684

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 730 AN: 1642

East Asian (EAS) AF: 0.0451 AC: 188 AN: 4164

South Asian (SAS) AF: 0.218 AC: 621 AN: 2854

European-Finnish (FIN) AF: 0.237 AC: 1730 AN: 7288

Middle Eastern (MID) AF: 0.476 AC: 78 AN: 164

European-Non Finnish (NFE) AF: 0.304 AC: 11270 AN: 37074

Other (OTH) AF: 0.232 AC: 287 AN: 1236

⚠️ 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: 0.326 Hom.: 1628

ExAC AF: 0.443 AC: 53200

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0020
DANN	Benign	0.20
DEOGEN2	Benign	0.017	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.76	N
PhyloP100		-2.5
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.044
Sift	Benign	0.32	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.039
ClinPred		0.012	T
GERP RS		-4.7
Varity_R		0.038
gMVP		0.012
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: rs28714612; hg19: chr14-105412009; COSMIC: COSV60906939;