12-132727540-G-A

Variant names:

• chr12-132727540-G-A
• rs35235926
• NM_015114.3:c.2616-97C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015114.3(ANKLE2):​c.2616-97C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,373,968 control chromosomes in the GnomAD database, including 12,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1293 hom., cov: 47)
  • Exomes 𝑓: 0.12 (10859 hom.)
• Consequence: ANKLE2 NM_015114.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.28
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-132727540-G-A is Benign according to our data. Variant chr12-132727540-G-A is described in ClinVar as Benign. ClinVar VariationId is 1257867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE2	NM_015114.3	MANE Select	c.2616-97C>T		intron	N/A	NP_055929.1	Q86XL3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE2	ENST00000357997.10	TSL:1 MANE Select	c.2616-97C>T		intron	N/A	ENSP00000350686.5	Q86XL3-1
	ANKLE2	ENST00000542282.5	TSL:1	c.681-97C>T		intron	N/A	ENSP00000437807.1	Q86XL3-3
	ANKLE2	ENST00000539605.5	TSL:1	n.9115-97C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18369 AN: 151568 Hom.: 1290 Cov.: 47

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0856

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.00772

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.123 AC: 150575 AN: 1222286 Hom.: 10859 AF XY: 0.124 AC XY: 75402 AN XY: 605904

African (AFR) AF: 0.142 AC: 3980 AN: 28076

American (AMR) AF: 0.0823 AC: 2779 AN: 33782

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 2829 AN: 21744

East Asian (EAS) AF: 0.00372 AC: 123 AN: 33082

South Asian (SAS) AF: 0.151 AC: 10826 AN: 71600

European-Finnish (FIN) AF: 0.0421 AC: 1772 AN: 42116

Middle Eastern (MID) AF: 0.129 AC: 670 AN: 5202

European-Non Finnish (NFE) AF: 0.129 AC: 121029 AN: 935602

Other (OTH) AF: 0.129 AC: 6567 AN: 51082

GnomAD4 genome AF: 0.121 AC: 18381 AN: 151682 Hom.: 1293 Cov.: 47 AF XY: 0.117 AC XY: 8648 AN XY: 74158

African (AFR) AF: 0.146 AC: 6021 AN: 41372

American (AMR) AF: 0.107 AC: 1627 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3460

East Asian (EAS) AF: 0.00794 AC: 41 AN: 5164

South Asian (SAS) AF: 0.159 AC: 762 AN: 4794

European-Finnish (FIN) AF: 0.0325 AC: 342 AN: 10518

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8783 AN: 67832

Other (OTH) AF: 0.124 AC: 261 AN: 2104

Alfa AF: 0.133 Hom.: 98

Bravo AF: 0.126

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.17
DANN	Benign	0.63
PhyloP100		-4.3
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: rs35235926; hg19: chr12-133304126;