19-19182607-G-C

Variant names:

• chr19-19182607-G-C
• rs1022797733
• NM_001145784.2:c.292C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145784.2(BORCS8):​c.292C>G​(p.Arg98Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BORCS8 NM_001145784.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• Publications: 0 publications found

Genes affected

BORCS8 (HGNC:37247): (BLOC-1 related complex subunit 8) Involved in heart development. Part of BORC complex. [provided by Alliance of Genome Resources, Apr 2022]

BORCS8-MEF2B (HGNC:39979): (BORCS8-MEF2B readthrough) This gene represents numerous read-through transcripts that span GeneID:729991 and 100271849. Many read-through transcripts are predicted to be nonsense-mediated decay (NMD) candidates, and are thought to be non-coding. Some transcripts are predicted to be capable of translation reinitiation at a downstream AUG, resulting in expression of at least one isoform of myocyte enhancer factor 2B (MEF2B) from this read-through locus. At least one additional MEF2B variant and isoform can be expressed from a downstream promoter, and is annotated on GeneID:100271849. [provided by RefSeq, Oct 2010]

MEF2B (HGNC:6995): (myocyte enhancer factor 2B) The product of this gene is a member of the MADS/MEF2 family of DNA binding proteins. The protein is thought to regulate gene expression, including expression of the smooth muscle myosin heavy chain gene. This region undergoes considerable alternative splicing, with transcripts supporting two non-overlapping loci (GeneID 729991 and 100271849) as well as numerous read-through transcripts that span both loci (annotated as GeneID 4207). Several isoforms of this protein are expressed from either this locus or from some of the read-through transcripts annotated on GeneID 4207. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145784.2. 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
	BORCS8	NM_001145784.2	MANE Select	c.292C>G	p.Arg98Gly	missense	Exon 4 of 6	NP_001139256.1	Q96FH0-1
	BORCS8	NM_001145783.2		c.292C>G	p.Arg98Gly	missense	Exon 4 of 4	NP_001139255.1	Q96FH0-2
	BORCS8-MEF2B	NM_005919.4		c.-140C>G		5_prime_UTR	Exon 2 of 10	NP_005910.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BORCS8	ENST00000462790.8	TSL:1 MANE Select	c.292C>G	p.Arg98Gly	missense	Exon 4 of 6	ENSP00000425864.1	Q96FH0-1
	BORCS8	ENST00000477565.3	TSL:1	c.292C>G	p.Arg98Gly	missense	Exon 4 of 4	ENSP00000424833.1	Q96FH0-2
	BORCS8-MEF2B	ENST00000514819.7	TSL:5	c.-13C>G		5_prime_UTR	Exon 2 of 9	ENSP00000454967.3	H3BNR1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399042 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690054

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078920

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.92	T
PhyloP100		5.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.68	P
Vest4		0.54
MutPred		0.77		Loss of MoRF binding (P = 0.0345)
MVP		0.20
ClinPred		0.94	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.81
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs1022797733; hg19: chr19-19293416;