NM_212556.4:c.1123G>C

Variant names:

• chr2-236196364-C-G
• rs777517326
• NM_212556.4:c.1123G>C

Variant summary

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

The NM_212556.4(ASB18):​c.1123G>C​(p.Val375Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,564,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: ASB18 NM_212556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.152
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212556.4. 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
	ASB18	NM_212556.4	MANE Select	c.1123G>C	p.Val375Leu	missense	Exon 5 of 6	NP_997721.2	Q6ZVZ8-1
	GBX2-AS1	NR_186035.1		n.229-17299C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASB18	ENST00000409749.8	TSL:1 MANE Select	c.1123G>C	p.Val375Leu	missense	Exon 5 of 6	ENSP00000386532.3	Q6ZVZ8-1
	ASB18	ENST00000645891.1		c.1036G>C	p.Val346Leu	missense	Exon 4 of 5	ENSP00000496134.1	Q6ZVZ8-2
	ASB18	ENST00000447030.1	TSL:4	c.262G>C	p.Val88Leu	missense	Exon 2 of 2	ENSP00000411434.1	H7C3E8

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151412 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000444 AC: 8 AN: 180328 AF XY: 0.0000628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000203

GnomAD4 exome AF: 0.0000920 AC: 130 AN: 1413086 Hom.: 0 Cov.: 30 AF XY: 0.0000945 AC XY: 66 AN XY: 698432

African (AFR) AF: 0.00 AC: 0 AN: 32270

American (AMR) AF: 0.00 AC: 0 AN: 37912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 36956

South Asian (SAS) AF: 0.0000624 AC: 5 AN: 80088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50342

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5566

European-Non Finnish (NFE) AF: 0.000108 AC: 117 AN: 1085928

Other (OTH) AF: 0.000119 AC: 7 AN: 58648

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151412 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73878

African (AFR) AF: 0.0000243 AC: 1 AN: 41122

American (AMR) AF: 0.0000659 AC: 1 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10438

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000169 AC: 2

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	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.6
DANN	Benign	0.38
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.15
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.013
Sift	Benign	0.35	T
Sift4G	Benign	0.67	T
Polyphen		0.010	B
Vest4		0.12
MutPred		0.46		Gain of ubiquitination at K370 (P = 0.2106)
MVP		0.15
MPC		1.1
ClinPred		0.017	T
GERP RS		-0.58
Varity_R		0.034
gMVP		0.24
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777517326; hg19: chr2-237105007;