20-35652812-T-TGGGCCA

Position:

• chr20-35652812-T-TGGGCCA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_006047.6(RBM12):​c.2510_2511insTGGCCC​(p.Gly836_Pro837dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,587,804 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (39 hom.)
• Consequence: RBM12 NM_006047.6 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.954

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 20-35652812-T-TGGGCCA is Benign according to our data. Variant chr20-35652812-T-TGGGCCA is described in ClinVar as [Benign]. Clinvar id is 3035644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00231 (348/150862) while in subpopulation AMR AF= 0.0202 (306/15118). AF 95% confidence interval is 0.0184. There are 3 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 348 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM12	NM_006047.6	c.2510_2511insTGGCCC	p.Gly836_Pro837dup	inframe_insertion	3/3	ENST00000374114.8
CPNE1	NM_152925.3	c.-1+11947_-1+11948insTGGCCC		intron_variant		ENST00000397443.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM12	ENST00000374114.8	c.2510_2511insTGGCCC	p.Gly836_Pro837dup	inframe_insertion	3/3	1	NM_006047.6	P1
CPNE1	ENST00000397443.7	c.-1+11947_-1+11948insTGGCCC		intron_variant		5	NM_152925.3	P1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 348 AN: 150744 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00242

GnomAD3 exomes AF: 0.00538 AC: 1288 AN: 239332 Hom.: 32 AF XY: 0.00399 AC XY: 520 AN XY: 130432

Gnomad AFR exome AF: 0.000723

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000385

Gnomad SAS exome AF: 0.0000679

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000652

Gnomad OTH exome AF: 0.00380

GnomAD4 exome AF: 0.00120 AC: 1721 AN: 1436942 Hom.: 39 Cov.: 31 AF XY: 0.00100 AC XY: 715 AN XY: 714084

Gnomad4 AFR exome AF: 0.000697

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0000405

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00231 AC: 348 AN: 150862 Hom.: 3 Cov.: 32 AF XY: 0.00220 AC XY: 162 AN XY: 73766

Gnomad4 AFR AF: 0.000676

Gnomad4 AMR AF: 0.0202

Gnomad4 ASJ AF: 0.000295

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000119

Gnomad4 OTH AF: 0.00240

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RBM12-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs569323785; hg19: chr20-34240734;