2-189676771-T-G

Variant names:

• chr2-189676771-T-G
• rs140832996
• NM_001378068.1:c.281T>G

Variant summary

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

The NM_001378068.1(ANKAR):​c.281T>G​(p.Leu94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,614,174 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L94P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (67 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (65 hom.)
• Consequence: ANKAR NM_001378068.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14

Genes affected

ANKAR (HGNC:26350): (ankyrin and armadillo repeat containing) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.00252074).
• BP6: Variant 2-189676771-T-G is Benign according to our data. Variant chr2-189676771-T-G is described in ClinVar as [Benign]. Clinvar id is 791881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKAR	NM_001378068.1	c.281T>G	p.Leu94Arg	missense_variant	Exon 2 of 23	ENST00000684021.1	NP_001364997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKAR	ENST00000684021.1	c.281T>G	p.Leu94Arg	missense_variant	Exon 2 of 23		NM_001378068.1	ENSP00000507233.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2471 AN: 152194 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00410 AC: 1029 AN: 251000 AF XY: 0.00315

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00176 AC: 2576 AN: 1461862 Hom.: 65 Cov.: 31 AF XY: 0.00156 AC XY: 1131 AN XY: 727226

Gnomad4 AFR exome AF: 0.0606 AC: 2030 AN: 33480

Gnomad4 AMR exome AF: 0.00288 AC: 129 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39696

Gnomad4 SAS exome AF: 0.0000927 AC: 8 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53400

Gnomad4 NFE exome AF: 0.000103 AC: 115 AN: 1112006

Gnomad4 Remaining exome AF: 0.00440 AC: 266 AN: 60396

GnomAD4 genome AF: 0.0163 AC: 2480 AN: 152312 Hom.: 67 Cov.: 32 AF XY: 0.0160 AC XY: 1194 AN XY: 74500

Gnomad4 AFR AF: 0.0561 AC: 0.0560554 AN: 0.0560554

Gnomad4 AMR AF: 0.00660 AC: 0.0066039 AN: 0.0066039

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000414079 AN: 0.000414079

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000103 AC: 0.000102902 AN: 0.000102902

Gnomad4 OTH AF: 0.0170 AC: 0.0170132 AN: 0.0170132

Alfa AF: 0.000231 Hom.: 31

Bravo AF: 0.0186

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0508 AC: 224

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00506 AC: 614

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.0041	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.58	.;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.58	N;N
REVEL	Benign	0.067
Sift	Benign	0.63	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.0030	B;B
Vest4		0.46
MVP		0.30
MPC		0.15
ClinPred		0.0028	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.11
Mutation Taster		=299/1	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs140832996; hg19: chr2-190541497; COSMIC: COSV104385750;