chr20-35652603-C-T

Position:

• chr20-35652603-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_006047.6(RBM12):​c.2720G>A​(p.Arg907Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RBM12 NM_006047.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83

Genes affected

RBM12 (HGNC:9898): (RNA binding motif protein 12) This gene encodes a protein that contains several RNA-binding motifs, potential transmembrane domains, and proline-rich regions. This gene and the gene for copine I overlap at map location 20q11.21. Alternative splicing in the 5' UTR results in four transcript variants. All variants encode the same protein. [provided by RefSeq, Nov 2010]

CPNE1 (HGNC:2314): (copine 1) Calcium-dependent membrane-binding proteins may regulate molecular events at the interface of the cell membrane and cytoplasm. This gene encodes a calcium-dependent protein that also contains two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. However, the encoded protein does not contain a predicted signal sequence or transmembrane domains. This protein has a broad tissue distribution and it may function in membrane trafficking. This gene and the gene for RNA binding motif protein 12 overlap at map location 20q11.21. Alternate splicing results in multiple transcript variants encoding different proteins. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1346795).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM12	NM_006047.6	c.2720G>A	p.Arg907Gln	missense_variant	3/3	ENST00000374114.8
CPNE1	NM_152925.3	c.-1+12157G>A		intron_variant		ENST00000397443.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM12	ENST00000374114.8	c.2720G>A	p.Arg907Gln	missense_variant	3/3	1	NM_006047.6	P1
CPNE1	ENST00000397443.7	c.-1+12157G>A		intron_variant		5	NM_152925.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Ambry Genetics

Feb 15, 2023

The c.2720G>A (p.R907Q) alteration is located in exon 3 (coding exon 1) of the RBM12 gene. This alteration results from a G to A substitution at nucleotide position 2720, causing the arginine (R) at amino acid position 907 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.00041
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	.;.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.26	N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.028	B;B;B
Vest4		0.37
MutPred		0.39		Loss of glycosylation at S906 (P = 0.1043);Loss of glycosylation at S906 (P = 0.1043);Loss of glycosylation at S906 (P = 0.1043);
MVP		0.20
MPC		0.23
ClinPred		0.62	D
GERP RS		4.4
Varity_R		0.23
gMVP		0.53

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: rs2033596853; hg19: chr20-34240525;