rs201127689

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-104948942-T-A
• chr14-104948942-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_138420.4(AHNAK2):​c.6509A>T​(p.Lys2170Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 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. K2170R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000024 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21786895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHNAK2	NM_138420.4	c.6509A>T	p.Lys2170Met	missense_variant	Exon 7 of 7	ENST00000333244.6	NP_612429.2
AHNAK2	NM_001350929.2	c.6209A>T	p.Lys2070Met	missense_variant	Exon 7 of 7		NP_001337858.1
AHNAK2	XM_024449463.2	c.6209A>T	p.Lys2070Met	missense_variant	Exon 7 of 7		XP_024305231.1
AHNAK2	XM_047430904.1	c.6209A>T	p.Lys2070Met	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>T	p.Lys2170Met	missense_variant	Exon 7 of 7	5	NM_138420.4	ENSP00000353114.4
AHNAK2	ENST00000557457.1	c.-221+4939A>T		intron_variant	Intron 1 of 2	1		ENSP00000450998.1
AHNAK2	ENST00000555122.1	n.6637A>T		non_coding_transcript_exon_variant	Exon 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.0000107 AC: 1 AN: 93190 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000309

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000237 AC: 28 AN: 1179134 Hom.: 1 Cov.: 104 AF XY: 0.0000272 AC XY: 16 AN XY: 588122

African (AFR) AF: 0.0000311 AC: 1 AN: 32150

American (AMR) AF: 0.0000248 AC: 1 AN: 40256

Ashkenazi Jewish (ASJ) AF: 0.0000490 AC: 1 AN: 20388

East Asian (EAS) AF: 0.00 AC: 0 AN: 38694

South Asian (SAS) AF: 0.00 AC: 0 AN: 72904

European-Finnish (FIN) AF: 0.0000225 AC: 1 AN: 44364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.0000240 AC: 21 AN: 876762

Other (OTH) AF: 0.0000607 AC: 3 AN: 49386

GnomAD4 genome AF: 0.0000107 AC: 1 AN: 93190 Hom.: 0 Cov.: 19 AF XY: 0.0000219 AC XY: 1 AN XY: 45630

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

African (AFR) AF: 0.00 AC: 0 AN: 34922

American (AMR) AF: 0.00 AC: 0 AN: 9598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1382

East Asian (EAS) AF: 0.00 AC: 0 AN: 4468

South Asian (SAS) AF: 0.00 AC: 0 AN: 2578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.0000309 AC: 1 AN: 32384

Other (OTH) AF: 0.00 AC: 0 AN: 1166

⚠️ 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.11
Sift	Benign	0.091	T
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.28		Gain of catalytic residue at V2165 (P = 0);
MVP		0.16
ClinPred		0.46	T
GERP RS		4.0
Varity_R		0.052
gMVP		0.011
Mutation Taster		=90/10	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: rs201127689; hg19: chr14-105415279;