14-104948942-T-C

Variant names:

• chr14-104948942-T-C
• rs201127689
• NM_138420.4:c.6509A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_138420.4(AHNAK2):​c.6509A>G​(p.Lys2170Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 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. K2170E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.044 (173 hom., cov: 19)
  • Exomes 𝑓: 0.12 (49964 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.84
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016698241).
• BP6: Variant 14-104948942-T-C is Benign according to our data. Variant chr14-104948942-T-C is described in ClinVar as [Benign]. Clinvar id is 402352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.6509A>G	p.Lys2170Arg	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.6209A>G	p.Lys2070Arg	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2	c.6209A>G	p.Lys2070Arg	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1	c.6209A>G	p.Lys2070Arg	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.6509A>G	p.Lys2170Arg	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-221+4939A>G		intron_variant	Intron 1 of 2	1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.6637A>G		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 3784 AN: 86654 Hom.: 174 Cov.: 19

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.0444

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0498

GnomAD2 exomes AF: 0.0966 AC: 19334 AN: 200092 AF XY: 0.104

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.00577

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.155

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.120 AC: 130577 AN: 1090618 Hom.: 49964 Cov.: 104 AF XY: 0.124 AC XY: 67073 AN XY: 542508

African (AFR) AF: 0.0423 AC: 1299 AN: 30718

American (AMR) AF: 0.0610 AC: 2183 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 4546 AN: 17334

East Asian (EAS) AF: 0.00334 AC: 126 AN: 37700

South Asian (SAS) AF: 0.158 AC: 10001 AN: 63388

European-Finnish (FIN) AF: 0.0828 AC: 3227 AN: 38988

Middle Eastern (MID) AF: 0.178 AC: 673 AN: 3776

European-Non Finnish (NFE) AF: 0.126 AC: 103087 AN: 818862

Other (OTH) AF: 0.123 AC: 5435 AN: 44078

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0436 AC: 3786 AN: 86786 Hom.: 173 Cov.: 19 AF XY: 0.0431 AC XY: 1841 AN XY: 42704

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

African (AFR) AF: 0.0440 AC: 1490 AN: 33898

American (AMR) AF: 0.0387 AC: 350 AN: 9040

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 78 AN: 1172

East Asian (EAS) AF: 0.00526 AC: 23 AN: 4372

South Asian (SAS) AF: 0.0445 AC: 105 AN: 2358

European-Finnish (FIN) AF: 0.0489 AC: 275 AN: 5618

Middle Eastern (MID) AF: 0.0943 AC: 10 AN: 106

European-Non Finnish (NFE) AF: 0.0482 AC: 1382 AN: 28682

Other (OTH) AF: 0.0480 AC: 52 AN: 1084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.353 Hom.: 3610

ExAC AF: 0.121 AC: 14301

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	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	0.080
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.13
Sift	Benign	0.78	T
Sift4G	Benign	0.68	T
Polyphen		0.99	D
Vest4		0.066
ClinPred		0.018	T
GERP RS		4.0
Varity_R		0.028
gMVP		0.0033
Mutation Taster		=99/1	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: rs201127689; hg19: chr14-105415279; COSMIC: COSV60910083; COSMIC: COSV60910083;