rs78699431

Variant names:

• chr1-244970326-C-CCCTCA
• rs78699431
• NM_032328.4:c.-90-3_-90-2insCCTCA

Your query was ambiguous. Multiple possible variants found:

• chr1-244970326-C-CCCTCA
• chr1-244970326-C-CCCTCG
• chr1-244970326-C-CCCTCT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_032328.4(DRC8):​c.-90-3_-90-2insCCTCA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,258 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: DRC8 NM_032328.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 0 publications found

Genes affected

DRC8 (HGNC:28166): (EF-hand calcium binding domain 2) The gene encodes a protein that contains two EF-hand calcium-binding domains although its function has yet to be determined. Alternatively spliced transcripts have been observed. [provided by RefSeq, Mar 2014]

LOC124900416 (HGNC:):

EFCAB2-AS1 (HGNC:58101):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.23517382 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 0 (no position change), new splice context is: cggcccctcctcccctcaAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032328.4. 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
	DRC8	NM_032328.4	MANE Select	c.-90-3_-90-2insCCTCA		splice_acceptor intron	N/A	NP_115704.1	Q5VUJ9-2
	EFCAB2-AS1	NR_111907.1		n.59-348_59-347insTGAGG		intron	N/A
	DRC8	NM_001290327.2		c.-175_-174insCCTCA		upstream_gene	N/A	NP_001277256.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFCAB2	ENST00000366523.6	TSL:3 MANE Select	c.-90-3_-90-2insCCTCA		splice_acceptor intron	N/A	ENSP00000355480.1	Q5VUJ9-2
	EFCAB2	ENST00000447569.6	TSL:2	c.-93_-92insCCTCA		5_prime_UTR	Exon 1 of 7	ENSP00000408661.2	Q5VUJ9-3
	EFCAB2	ENST00000923177.1		c.-93_-92insCCTCA		5_prime_UTR	Exon 1 of 6	ENSP00000593236.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345258 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 665630

African (AFR) AF: 0.00 AC: 0 AN: 29802

American (AMR) AF: 0.00 AC: 0 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24502

East Asian (EAS) AF: 0.00 AC: 0 AN: 33820

South Asian (SAS) AF: 0.00 AC: 0 AN: 77956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1047762

Other (OTH) AF: 0.00 AC: 0 AN: 56516

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

Splicing

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

Other links and lift over

dbSNP: rs78699431; hg19: chr1-245133628;