chr2-23757889-T-C

Variant names:

• chr2-23757889-T-C
• rs201429059
• NM_017552.4:c.3607A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017552.4(ATAD2B):​c.3607A>G​(p.Met1203Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000749 in 1,601,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: ATAD2B NM_017552.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.907

Genes affected

ATAD2B (HGNC:29230): (ATPase family AAA domain containing 2B) The protein encoded by this gene belongs to the AAA ATPase family. This family member includes an N-terminal bromodomain. It has been found to be localized to the nucleus, partly to replication sites, consistent with a chromatin-related function. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020368963).
• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATAD2B	NM_017552.4	c.3607A>G	p.Met1203Val	missense_variant	Exon 25 of 28	ENST00000238789.10	NP_060022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATAD2B	ENST00000238789.10	c.3607A>G	p.Met1203Val	missense_variant	Exon 25 of 28	5	NM_017552.4	ENSP00000238789.5
ATAD2B	ENST00000381024.4	c.1432A>G	p.Met478Val	missense_variant	Exon 9 of 12	1		ENSP00000370412.4
ATAD2B	ENST00000474583.5	n.2752A>G		non_coding_transcript_exon_variant	Exon 16 of 19	2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000102 AC: 24 AN: 235648 Hom.: 0 AF XY: 0.0000861 AC XY: 11 AN XY: 127746

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.000646

Gnomad SAS exome AF: 0.000148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.0000732 AC: 106 AN: 1448942 Hom.: 0 Cov.: 31 AF XY: 0.0000652 AC XY: 47 AN XY: 720486

Gnomad4 AFR exome AF: 0.0000927

Gnomad4 AMR exome AF: 0.0000241

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.000404

Gnomad4 SAS exome AF: 0.000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000271

Gnomad4 OTH exome AF: 0.000670

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74478

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000776 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3607A>G (p.M1203V) alteration is located in exon 25 (coding exon 25) of the ATAD2B gene. This alteration results from a A to G substitution at nucleotide position 3607, causing the methionine (M) at amino acid position 1203 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	Benign	0.059
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.81
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.69	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.21
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Vest4		0.15
MVP		0.56
MPC		0.49
ClinPred		0.0084	T
GERP RS		3.1
gMVP		0.16

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: rs201429059; hg19: chr2-23980759; COSMIC: COSV53198761; COSMIC: COSV53198761;