12-132755103-C-G

Variant names:

• chr12-132755103-C-G
• rs200911469
• NM_015114.3:c.212G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015114.3(ANKLE2):​c.212G>C​(p.Arg71Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R71Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANKLE2 NM_015114.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

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]

ANKLE2 Gene-Disease associations (from GenCC):

• microcephaly 16, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015114.3. 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
	ANKLE2	NM_015114.3	MANE Select	c.212G>C	p.Arg71Pro	missense	Exon 2 of 13	NP_055929.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE2	ENST00000357997.10	TSL:1 MANE Select	c.212G>C	p.Arg71Pro	missense	Exon 2 of 13	ENSP00000350686.5
	ANKLE2	ENST00000539605.5	TSL:1	n.6711G>C		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.59		Loss of stability (P = 0.0913)
MVP		0.30
MPC		0.50
ClinPred		0.93	D
GERP RS		2.6
Varity_R		0.54
gMVP		0.42
Mutation Taster		=48/52	disease causing

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: rs200911469; hg19: chr12-133331689;