12-56245517-C-T

Variant names:

• chr12-56245517-C-T
• rs1278962898
• NM_173595.4:c.2264G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173595.4(ANKRD52):​c.2264G>A​(p.Arg755His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R755C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKRD52 NM_173595.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

Genes affected

ANKRD52 (HGNC:26614): (ankyrin repeat domain 52)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD52	NM_173595.4	c.2264G>A	p.Arg755His	missense_variant	Exon 21 of 28	ENST00000267116.8	NP_775866.2
ANKRD52	XM_017019183.2	c.2261G>A	p.Arg754His	missense_variant	Exon 20 of 27		XP_016874672.1
ANKRD52	XM_011538197.3	c.2081G>A	p.Arg694His	missense_variant	Exon 20 of 27		XP_011536499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD52	ENST00000267116.8	c.2264G>A	p.Arg755His	missense_variant	Exon 21 of 28	1	NM_173595.4	ENSP00000267116.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459176 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725908

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2264G>A (p.R755H) alteration is located in exon 21 (coding exon 21) of the ANKRD52 gene. This alteration results from a G to A substitution at nucleotide position 2264, causing the arginine (R) at amino acid position 755 to be replaced by a histidine (H). 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	0.61
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.9	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.62		Gain of catalytic residue at K753 (P = 8e-04);
MVP		0.76
MPC		2.1
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.44
gMVP		0.79

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: rs1278962898; hg19: chr12-56639301;