rs2363956

Variant names:

• chr19-17283315-T-G
• rs2363956
• NM_152363.6:c.551T>G

Variant summary

Our verdict is Benign. The variant received -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. 13/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 145 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152363.6. 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
	ANKLE1	NM_152363.6	MANE Select	c.551T>G	p.Leu184Trp	missense	Exon 5 of 9	NP_689576.6
	ANKLE1	NM_001278444.2		c.551T>G	p.Leu184Trp	missense	Exon 5 of 8	NP_001265373.2
	ANKLE1	NM_001278443.2		c.518T>G	p.Leu173Trp	missense	Exon 5 of 9	NP_001265372.2	A0A494C092

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE1	ENST00000404085.7	TSL:2 MANE Select	c.551T>G	p.Leu184Trp	missense	Exon 5 of 9	ENSP00000384008.3	Q8NAG6-2
	ANKLE1	ENST00000394458.7	TSL:1	c.713T>G	p.Leu238Trp	missense	Exon 5 of 9	ENSP00000377971.4	A0A499FJM0
	ANKLE1	ENST00000598347.2	TSL:2	c.551T>G	p.Leu184Trp	missense	Exon 5 of 8	ENSP00000470895.2	M0R002

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

GnomAD2 exomes AF: 0.483 AC: 120923 AN: 250576 AF XY: 0.486

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 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

African (AFR) AF: 0.499 AC: 16701 AN: 33476

American (AMR) AF: 0.398 AC: 17802 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 13171 AN: 26134

East Asian (EAS) AF: 0.321 AC: 12729 AN: 39700

South Asian (SAS) AF: 0.474 AC: 40845 AN: 86254

European-Finnish (FIN) AF: 0.562 AC: 29786 AN: 52988

Middle Eastern (MID) AF: 0.508 AC: 2929 AN: 5768

European-Non Finnish (NFE) AF: 0.516 AC: 574008 AN: 1111790

Other (OTH) AF: 0.507 AC: 30607 AN: 60366

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

African (AFR) AF: 0.502 AC: 20792 AN: 41398

American (AMR) AF: 0.438 AC: 6687 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1763 AN: 3466

East Asian (EAS) AF: 0.318 AC: 1636 AN: 5150

South Asian (SAS) AF: 0.479 AC: 2304 AN: 4814

European-Finnish (FIN) AF: 0.569 AC: 6004 AN: 10548

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 35006 AN: 67944

Other (OTH) AF: 0.487 AC: 1024 AN: 2104

Alfa AF: 0.507 Hom.: 95591

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 v4.9

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
MetaSVM	Benign	-0.93	T
PhyloP100		0.98
PrimateAI	Benign	0.36	T
REVEL	Benign	0.25
Sift4G	Benign	0.19	T
Vest4		0.14
MPC		0.92
ClinPred		0.0095	T
GERP RS		2.3
gMVP		0.39
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2363956; hg19: chr19-17394124; COSMIC: COSV63920460; COSMIC: COSV63920460;