2-236214769-C-G

Position:

• chr2-236214769-C-G

Variant summary

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

The NM_212556.4(ASB18):​c.694G>C​(p.Asp232His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ASB18 NM_212556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.531

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=0.2509026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASB18	NM_212556.4	c.694G>C	p.Asp232His	missense_variant	4/6	ENST00000409749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASB18	ENST00000409749.8	c.694G>C	p.Asp232His	missense_variant	4/6	1	NM_212556.4	P1
GBX2-AS1	ENST00000415226.1	n.224-44738C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 23, 2016

The D232H variant in the ASB18 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Sufficient data from control individuals in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium data sets were not available to assess whether the D232H variant may be a common benign variant in the general population; however, this variant has not been detected at any significant frequency previously in the internal database at GeneDx. The D232H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D232H as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	.;N;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.77	.;N;N
REVEL	Benign	0.12
Sift	Benign	0.20	.;T;T
Sift4G	Benign	0.44	.;T;.
Polyphen		0.86	.;P;.
Vest4		0.16
MutPred		0.43		.;Gain of MoRF binding (P = 0.046);.;
MVP		0.49
MPC		2.4
ClinPred		0.52	D
GERP RS		2.8
Varity_R		0.094
gMVP		0.34

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: rs1057518421; hg19: chr2-237123412;