2-236214423-C-T

Variant names:

• chr2-236214423-C-T
• rs1468660874
• NM_212556.4:c.1040G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_212556.4(ASB18):​c.1040G>A​(p.Arg347His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,410,544 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: 0.0000021 (0 hom.)
• Consequence: ASB18 NM_212556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.254

Genes affected

ASB18 (HGNC:19770): (ankyrin repeat and SOCS box containing 18) The protein encoded by this gene is a member of the ankyrin repeat and SOCS box-containing (ASB) family of proteins. They contain ankyrin repeat sequence and a SOCS box domain. The SOCS box serves to couple suppressor of cytokine signalling (SOCS) proteins and their binding partners with the elongin B and C complex, possibly targeting them for degradation. [provided by RefSeq, Feb 2017]

GBX2-AS1 (HGNC:55714): (GBX2 and ASB18 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16604331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASB18	NM_212556.4	c.1040G>A	p.Arg347His	missense_variant	Exon 4 of 6	ENST00000409749.8	NP_997721.2
GBX2-AS1	NR_186035.1	n.*198C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASB18	ENST00000409749.8	c.1040G>A	p.Arg347His	missense_variant	Exon 4 of 6	1	NM_212556.4	ENSP00000386532.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1410544 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 698690

Gnomad4 AFR exome AF: 0.0000313

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: 9.15e-7

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1040G>A (p.R347H) alteration is located in exon 4 (coding exon 4) of the ASB18 gene. This alteration results from a G to A substitution at nucleotide position 1040, causing the arginine (R) at amino acid position 347 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	Benign	0.087
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	.;N;N
REVEL	Benign	0.056
Sift	Benign	0.45	.;T;T
Sift4G	Benign	0.58	.;T;D
Polyphen		1.0	.;D;.
Vest4		0.090
MVP		0.24
MPC		2.2
ClinPred		0.71	D
GERP RS		-0.34
Varity_R		0.029
gMVP		0.22

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: rs1468660874; hg19: chr2-237123066;