chr6-118481910-A-AT

Position:

• chr6-118481910-A-AT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PVS1 BS2_Supporting

The NM_001042475.3(CEP85L):​c.1613dupA​(p.Asn538fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000384 in 1,563,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CEP85L NM_001042475.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

Genes affected

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

LOC105377971 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP85L	NM_001042475.3	c.1613dupA	p.Asn538fs	frameshift_variant	8/13	ENST00000368491.8	NP_001035940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP85L	ENST00000368491.8	c.1613dupA	p.Asn538fs	frameshift_variant	8/13	1	NM_001042475.3	ENSP00000357477.3
CEP85L	ENST00000434604.5	c.1622dupA	p.Asn541fs	frameshift_variant	9/9	1		ENSP00000392131.1
CEP85L	ENST00000368488.9	c.1622dupA	p.Asn541fs	frameshift_variant	9/14	5		ENSP00000357474.5

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1412854 Hom.: 0 Cov.: 28 AF XY: 0.00000142 AC XY: 1 AN XY: 701944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000525

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: 0.00000276

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150204 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 73200

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

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: rs1554203314; hg19: chr6-118803073;