2-189689587-A-G

Position:

• chr2-189689587-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378068.1(ANKAR):​c.662A>G​(p.Glu221Gly) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKAR NM_001378068.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.906

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06303769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKAR	NM_001378068.1	c.662A>G	p.Glu221Gly	missense_variant	3/23	ENST00000684021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKAR	ENST00000684021.1	c.662A>G	p.Glu221Gly	missense_variant	3/23		NM_001378068.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2024

The c.662A>G (p.E221G) alteration is located in exon 3 (coding exon 2) of the ANKAR gene. This alteration results from a A to G substitution at nucleotide position 662, causing the glutamic acid (E) at amino acid position 221 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0040	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.0090
Sift	Benign	0.49	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.10	B;B
Vest4		0.13
MutPred		0.33		Loss of stability (P = 0.0625);Loss of stability (P = 0.0625);
MVP		0.67
MPC		0.14
ClinPred		0.19	T
GERP RS		2.1
Varity_R		0.095
gMVP		0.35

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: rs2036113204; hg19: chr2-190554313;