rs2363956

chr19-17283315-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152363.6(ANKLE1):c.551T>G(p.Leu184Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,613,080 control chromosomes in the GnomAD database, including 206,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (18975 hom., cov: 31)
  • Exomes 𝑓: 0.51 (187900 hom.)
• Consequence: ANKLE1 NM_152363.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.985

Genes affected

ANKLE1 (HGNC:26812): (ankyrin repeat and LEM domain containing 1) Enables endonuclease activity. Involved in positive regulation of response to DNA damage stimulus and protein export from nucleus. Located in cytosol and nucleoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3133883E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKLE1	NM_152363.6	c.551T>G	p.Leu184Trp	missense_variant	5/9	ENST00000404085.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKLE1	ENST00000404085.7	c.551T>G	p.Leu184Trp	missense_variant	5/9	2	NM_152363.6	P2

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75739 AN: 151762 Hom.: 18954 Cov.: 31

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.483

GnomAD3 exomes AF: 0.483 AC: 120923 AN: 250576 Hom.: 29811 AF XY: 0.486 AC XY: 65943 AN XY: 135588

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.312

Gnomad SAS exome AF: 0.476

Gnomad FIN exome AF: 0.564

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.490

GnomAD4 exome AF: 0.505 AC: 738578 AN: 1461200 Hom.: 187900 Cov.: 85 AF XY: 0.504 AC XY: 366442 AN XY: 726894

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.504

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.562

Gnomad4 NFE exome AF: 0.516

Gnomad4 OTH exome AF: 0.507

GnomAD4 genome AF: 0.499 AC: 75812 AN: 151880 Hom.: 18975 Cov.: 31 AF XY: 0.499 AC XY: 37012 AN XY: 74218

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.515

Gnomad4 OTH AF: 0.487

Alfa AF: 0.510 Hom.: 49772

Bravo AF: 0.487

TwinsUK AF: 0.498 AC: 1848

ALSPAC AF: 0.508 AC: 1958

ESP6500AA AF: 0.500 AC: 2204

ESP6500EA AF: 0.519 AC: 4461

ExAC AF: 0.486 AC: 58966

Asia WGS AF: 0.429 AC: 1490 AN: 3478

EpiCase AF: 0.517

EpiControl AF: 0.522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Benign	0.95
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.37	T;.
MetaRNN	Benign	0.00013	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.36	T
REVEL	Benign	0.25
Sift4G	Benign	0.19	T;T
Vest4		0.14
MPC		0.92
ClinPred		0.0095	T
GERP RS		2.3
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs2363956; hg19: chr19-17394124; COSMIC: COSV63920460; COSMIC: COSV63920460;