rs863225465

chr12-132734559-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_015114.3(ANKLE2):c.1717C>G(p.Leu573Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKLE2 NM_015114.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.28

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-132734559-G-C is Pathogenic according to our data. Variant chr12-132734559-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218246.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30575043).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKLE2	NM_015114.3	c.1717C>G	p.Leu573Val	missense_variant	10/13	ENST00000357997.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKLE2	ENST00000357997.10	c.1717C>G	p.Leu573Val	missense_variant	10/13	1	NM_015114.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 16, primary, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 25, 2014

- -

Microcephaly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 25, 2014

Overexpression of human cDNA carring this variant does not rescue mutant fly -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Benign	0.038	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.24		Loss of helix (P = 0.1299);
MVP		0.41
MPC		0.50
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.25
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs863225465; hg19: chr12-133311145;