10-97578273-C-G

Position:

• chr10-97578273-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001346793.2(ANKRD2):​c.223C>G​(p.Leu75Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANKRD2 NM_001346793.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

Genes affected

ANKRD2 (HGNC:495): (ankyrin repeat domain 2) This gene encodes a protein that belongs to the muscle ankyrin repeat protein (MARP) family. A similar gene in rodents is a component of a muscle stress response pathway and plays a role in the stretch-response associated with slow muscle function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD2	NM_001346793.2	c.223C>G	p.Leu75Val	missense_variant	3/9	ENST00000370655.6	NP_001333722.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD2	ENST00000370655.6	c.223C>G	p.Leu75Val	missense_variant	3/9	1	NM_001346793.2	ENSP00000359689
ANKRD2	ENST00000307518.9	c.304C>G	p.Leu102Val	missense_variant	3/9	1		ENSP00000306163	P1
ANKRD2	ENST00000298808.9	c.304C>G	p.Leu102Val	missense_variant	3/8	1		ENSP00000298808
ANKRD2	ENST00000455090.1	c.223C>G	p.Leu75Val	missense_variant	3/8	1		ENSP00000403114

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

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

Mar 11, 2024

The c.304C>G (p.L102V) alteration is located in exon 3 (coding exon 3) of the ANKRD2 gene. This alteration results from a C to G substitution at nucleotide position 304, causing the leucine (L) at amino acid position 102 to be replaced by a valine (V). 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	Pathogenic	0.71
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	M;M;.;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.61	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.58
MutPred		0.23		Gain of MoRF binding (P = 0.109);Gain of MoRF binding (P = 0.109);.;.;
MVP		0.77
MPC		0.78
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.25
gMVP		0.69

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: rs2040851526; hg19: chr10-99338030;