20-35652764-T-C

Position:

• chr20-35652764-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006047.6(RBM12):​c.2559A>G​(p.Pro853Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,612,590 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (63 hom.)
• Consequence: RBM12 NM_006047.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.97

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]

ENSG00000272897 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 20-35652764-T-C is Benign according to our data. Variant chr20-35652764-T-C is described in ClinVar as [Benign]. Clinvar id is 775434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00671 (9791/1460238) while in subpopulation MID AF= 0.0347 (200/5760). AF 95% confidence interval is 0.0308. There are 63 homozygotes in gnomad4_exome. There are 4888 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 889 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM12	NM_006047.6	c.2559A>G	p.Pro853Pro	synonymous_variant	3/3	ENST00000374114.8	NP_006038.2
CPNE1	NM_152925.3	c.-1+11996A>G		intron_variant		ENST00000397443.7	NP_690902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM12	ENST00000374114.8	c.2559A>G	p.Pro853Pro	synonymous_variant	3/3	1	NM_006047.6	ENSP00000363228.3
CPNE1	ENST00000397443.7	c.-1+11996A>G		intron_variant		5	NM_152925.3	ENSP00000380585.1
CPNE1	ENST00000437340.5	c.-1+12038A>G		intron_variant		1		ENSP00000415597.1
ENSG00000272897	ENST00000541176.2	n.*32+2438A>G		intron_variant		2		ENSP00000443983.2

Frequencies

GnomAD3 genomes AF: 0.00585 AC: 891 AN: 152234 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00732

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00660 AC: 1635 AN: 247842 Hom.: 12 AF XY: 0.00667 AC XY: 897 AN XY: 134538

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00217

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00876

GnomAD4 exome AF: 0.00671 AC: 9791 AN: 1460238 Hom.: 63 Cov.: 31 AF XY: 0.00673 AC XY: 4888 AN XY: 726296

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00535

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00265

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00671

Gnomad4 OTH exome AF: 0.00794

GnomAD4 genome AF: 0.00584 AC: 889 AN: 152352 Hom.: 5 Cov.: 32 AF XY: 0.00603 AC XY: 449 AN XY: 74506

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00733

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00803 Hom.: 6

Bravo AF: 0.00567

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.82

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: rs74880624; hg19: chr20-34240686;