2-189689917-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.992A>G(p.Lys331Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,396,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ANKAR NM_001378068.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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=0.04613787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKAR	NM_001378068.1	c.992A>G	p.Lys331Arg	missense_variant	3/23	ENST00000684021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKAR	ENST00000684021.1	c.992A>G	p.Lys331Arg	missense_variant	3/23		NM_001378068.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000155 AC: 3 AN: 193682 Hom.: 0 AF XY: 0.00000945 AC XY: 1 AN XY: 105796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000115 AC: 16 AN: 1396760 Hom.: 0 Cov.: 30 AF XY: 0.00000722 AC XY: 5 AN XY: 692426

Gnomad4 AFR exome AF: 0.0000329

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

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

Feb 27, 2023

The c.992A>G (p.K331R) 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 992, causing the lysine (K) at amino acid position 331 to be replaced by an arginine (R). 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	0.072
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0040	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.94	N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.015
Sift	Benign	0.42	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.0070	B;B
Vest4		0.082
MutPred		0.21		Loss of methylation at K331 (P = 0.0401);Loss of methylation at K331 (P = 0.0401);
MVP		0.55
MPC		0.081
ClinPred		0.091	T
GERP RS		0.84
Varity_R		0.032
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs773295578; hg19: chr2-190554643;