chr14-104945801-A-G

Variant names:

• chr14-104945801-A-G
• rs200384326
• NM_138420.4:c.9650T>C

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.9650T>C​(p.Leu3217Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. L3217I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (668 hom., cov: 21)
  • Exomes 𝑓: 0.32 (142817 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHNAK2 NM_138420.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.281
• Publications: 19 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=0.004053861).
• BP6: Variant 14-104945801-A-G is Benign according to our data. Variant chr14-104945801-A-G is described in ClinVar as Benign. ClinVar VariationId is 402349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.9650T>C	p.Leu3217Pro	missense	Exon 7 of 7	NP_612429.2
	AHNAK2	NM_001350929.2		c.9350T>C	p.Leu3117Pro	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.9650T>C	p.Leu3217Pro	missense	Exon 7 of 7	ENSP00000353114.4
	AHNAK2	ENST00000557457.1	TSL:1	c.-220-4823T>C		intron	N/A	ENSP00000450998.1
	AHNAK2	ENST00000555122.1	TSL:5	n.9778T>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.100 AC: 8316 AN: 82918 Hom.: 669 Cov.: 21

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0291

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0949

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.162 AC: 29520 AN: 182330 AF XY: 0.165

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0963

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.227

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.315 AC: 303377 AN: 962178 Hom.: 142817 Cov.: 82 AF XY: 0.320 AC XY: 151741 AN XY: 474576

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

African (AFR) AF: 0.0676 AC: 1669 AN: 24678

American (AMR) AF: 0.132 AC: 4009 AN: 30336

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 8362 AN: 15388

East Asian (EAS) AF: 0.0165 AC: 553 AN: 33572

South Asian (SAS) AF: 0.320 AC: 16909 AN: 52788

European-Finnish (FIN) AF: 0.203 AC: 6911 AN: 34116

Middle Eastern (MID) AF: 0.409 AC: 1293 AN: 3164

European-Non Finnish (NFE) AF: 0.345 AC: 251569 AN: 729728

Other (OTH) AF: 0.315 AC: 12102 AN: 38408

⚠️ 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: 0.100 AC: 8312 AN: 83024 Hom.: 668 Cov.: 21 AF XY: 0.0938 AC XY: 3829 AN XY: 40828

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

African (AFR) AF: 0.0486 AC: 1409 AN: 29002

American (AMR) AF: 0.0936 AC: 846 AN: 9042

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 249 AN: 1144

East Asian (EAS) AF: 0.0289 AC: 114 AN: 3944

South Asian (SAS) AF: 0.127 AC: 311 AN: 2456

European-Finnish (FIN) AF: 0.0949 AC: 557 AN: 5868

Middle Eastern (MID) AF: 0.290 AC: 36 AN: 124

European-Non Finnish (NFE) AF: 0.154 AC: 4608 AN: 29900

Other (OTH) AF: 0.123 AC: 134 AN: 1092

⚠️ 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: 0.324 Hom.: 2467

ExAC AF: 0.194 AC: 23139

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.13
DANN	Benign	0.30
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00065	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		-0.28
PrimateAI	Benign	0.20	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.041
Sift	Benign	0.11	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.055
ClinPred		0.0026	T
GERP RS		2.6
Varity_R		0.043
gMVP		0.010
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: rs200384326; hg19: chr14-105412138; COSMIC: COSV60906872;