rs12721503

Positions:

• chr2-201163219-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000457277.5(CFLAR):​c.*139T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,271,616 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (58 hom., cov: 32)
  • Exomes 𝑓: 0.020 (290 hom.)
• Consequence: CFLAR ENST00000457277.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553

Genes affected

CFLAR (HGNC:1876): (CASP8 and FADD like apoptosis regulator) The protein encoded by this gene is a regulator of apoptosis and is structurally similar to caspase-8. However, the encoded protein lacks caspase activity and appears to be itself cleaved into two peptides by caspase-8. Several transcript variants encoding different isoforms have been found for this gene, and partial evidence for several more variants exists. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0179 (2722/152304) while in subpopulation SAS AF= 0.0267 (129/4828). AF 95% confidence interval is 0.023. There are 58 homozygotes in gnomad4. There are 1474 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2722 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.1305-616T>C		intron_variant		ENST00000309955.8	NP_003870.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.1305-616T>C		intron_variant		1	NM_003879.7	ENSP00000312455	P2

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2721 AN: 152186 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0719

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0198 AC: 22160 AN: 1119312 Hom.: 290 Cov.: 14 AF XY: 0.0200 AC XY: 10846 AN XY: 541396

Gnomad4 AFR exome AF: 0.00362

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0431

Gnomad4 EAS exome AF: 0.000894

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.0765

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0214

GnomAD4 genome AF: 0.0179 AC: 2722 AN: 152304 Hom.: 58 Cov.: 32 AF XY: 0.0198 AC XY: 1474 AN XY: 74468

Gnomad4 AFR AF: 0.00397

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.0719

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0180 Hom.: 4

Bravo AF: 0.0134

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.9
DANN	Benign	0.77

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: rs12721503; hg19: chr2-202027942;