12-132727252-G-A

Variant names:

• chr12-132727252-G-A
• rs999809276
• NM_015114.3:c.2807C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015114.3(ANKLE2):​c.2807C>T​(p.Ala936Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000057 in 1,404,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: ANKLE2 NM_015114.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

Genes affected

ANKLE2 (HGNC:29101): (ankyrin repeat and LEM domain containing 2) This gene encodes a member of the LEM family of inner nuclear membrane proteins. The encoded protein functions as a mitotic regulator through postmitotic formation of the nuclear envelope. Mutations in this gene cause morphology defects in the nuclear envelope and BAF hyperphosphorylation. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15792125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKLE2	NM_015114.3	c.2807C>T	p.Ala936Val	missense_variant	Exon 13 of 13	ENST00000357997.10	NP_055929.1
ANKLE2	XM_005266159.4	c.2621C>T	p.Ala874Val	missense_variant	Exon 13 of 13		XP_005266216.1
ANKLE2	XM_024448899.2	c.1496C>T	p.Ala499Val	missense_variant	Exon 9 of 9		XP_024304667.1
ANKLE2	XM_006719735.2	c.*172C>T		3_prime_UTR_variant	Exon 12 of 12		XP_006719798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKLE2	ENST00000357997.10	c.2807C>T	p.Ala936Val	missense_variant	Exon 13 of 13	1	NM_015114.3	ENSP00000350686.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000570 AC: 8 AN: 1404570 Hom.: 0 Cov.: 31 AF XY: 0.00000577 AC XY: 4 AN XY: 693012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000274

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.0000516

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2807C>T (p.A936V) alteration is located in exon 13 (coding exon 13) of the ANKLE2 gene. This alteration results from a C to T substitution at nucleotide position 2807, causing the alanine (A) at amino acid position 936 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.65	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.19	B;.;.
Vest4		0.12
MutPred		0.32		Loss of disorder (P = 0.1297);.;.;
MVP		0.54
MPC		0.093
ClinPred		0.14	T
GERP RS		6.0
Varity_R		0.057
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs999809276; hg19: chr12-133303838;