2-96839641-A-G

Variant names:

• chr2-96839641-A-G
• rs1019970684
• NM_144994.8:c.826T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144994.8(ANKRD23):​c.826T>C​(p.Ser276Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000198 in 1,518,262 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ANKRD23 NM_144994.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

Genes affected

ANKRD23 (HGNC:24470): (ankyrin repeat domain 23) This gene is a member of the muscle ankyrin repeat protein (MARP) family and encodes a protein with four tandem ankyrin-like repeats. The protein is localized to the nucleus, functioning as a transcriptional regulator. Expression of this protein is induced during recovery following starvation. [provided by RefSeq, Jul 2008]

ANKRD39 (HGNC:28640): (ankyrin repeat domain 39) Predicted to contribute to ubiquitin-protein transferase activity. Predicted to be involved in protein K6-linked ubiquitination. Predicted to be part of BRCA1-A complex and BRCA1-BARD1 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20070219).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144994.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD23	NM_144994.8	MANE Select	c.826T>C	p.Ser276Pro	missense	Exon 9 of 9	NP_659431.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD23	ENST00000318357.9	TSL:1 MANE Select	c.826T>C	p.Ser276Pro	missense	Exon 9 of 9	ENSP00000321679.4	Q86SG2-1
	ANKRD23	ENST00000962363.1		c.835T>C	p.Ser279Pro	missense	Exon 9 of 9	ENSP00000632422.1
	ANKRD23	ENST00000870651.1		c.829T>C	p.Ser277Pro	missense	Exon 9 of 9	ENSP00000540710.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1366068 Hom.: 0 Cov.: 32 AF XY: 0.00000299 AC XY: 2 AN XY: 668830

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30838

American (AMR) AF: 0.00 AC: 0 AN: 31578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20974

East Asian (EAS) AF: 0.00 AC: 0 AN: 37798

South Asian (SAS) AF: 0.00 AC: 0 AN: 73950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4360

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1063024

Other (OTH) AF: 0.00 AC: 0 AN: 56062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.93	P
Vest4		0.36
MutPred		0.54		Loss of MoRF binding (P = 0.0553)
MVP		0.34
MPC		0.49
ClinPred		0.61	D
GERP RS		2.6
Varity_R		0.27
gMVP		0.52
Mutation Taster		=78/22	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

Other links and lift over

dbSNP: rs1019970684; hg19: chr2-97505378;