2-201160898-A-G

Variant names:

• chr2-201160898-A-G
• rs1594
• NM_003879.7:c.1260A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_003879.7(CFLAR):​c.1260A>G​(p.Pro420Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,610,572 control chromosomes in the GnomAD database, including 198,259 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 0.47 (17283 hom., cov: 28)
  • Exomes 𝑓: 0.49 (180976 hom.)
• Consequence: CFLAR NM_003879.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.78
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003879.7. 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
	CFLAR	NM_003879.7	MANE Select	c.1260A>G	p.Pro420Pro	synonymous	Exon 9 of 10	NP_003870.4
	CFLAR	NM_001127183.4		c.1260A>G	p.Pro420Pro	synonymous	Exon 9 of 10	NP_001120655.1	O15519-1
	CFLAR	NM_001308042.3		c.1260A>G	p.Pro420Pro	synonymous	Exon 9 of 10	NP_001294971.1	O15519-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFLAR	ENST00000309955.8	TSL:1 MANE Select	c.1260A>G	p.Pro420Pro	synonymous	Exon 9 of 10	ENSP00000312455.2	O15519-1
	CFLAR	ENST00000423241.6	TSL:1	c.1260A>G	p.Pro420Pro	synonymous	Exon 9 of 10	ENSP00000399420.2	O15519-1
	CFLAR	ENST00000457277.5	TSL:1	c.1260A>G	p.Pro420Pro	synonymous	Exon 8 of 9	ENSP00000411535.1	O15519-11

Frequencies

GnomAD3 genomes AF: 0.474 AC: 71816 AN: 151462 Hom.: 17262 Cov.: 28

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.446 AC: 111545 AN: 250140 AF XY: 0.446

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.493 AC: 719053 AN: 1458992 Hom.: 180976 Cov.: 35 AF XY: 0.489 AC XY: 355208 AN XY: 725968

African (AFR) AF: 0.467 AC: 15615 AN: 33428

American (AMR) AF: 0.359 AC: 16065 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 13875 AN: 26122

East Asian (EAS) AF: 0.219 AC: 8689 AN: 39696

South Asian (SAS) AF: 0.369 AC: 31847 AN: 86210

European-Finnish (FIN) AF: 0.481 AC: 25694 AN: 53396

Middle Eastern (MID) AF: 0.415 AC: 2388 AN: 5758

European-Non Finnish (NFE) AF: 0.519 AC: 575824 AN: 1109360

Other (OTH) AF: 0.482 AC: 29056 AN: 60314

GnomAD4 genome AF: 0.474 AC: 71877 AN: 151580 Hom.: 17283 Cov.: 28 AF XY: 0.467 AC XY: 34618 AN XY: 74056

African (AFR) AF: 0.466 AC: 19240 AN: 41300

American (AMR) AF: 0.412 AC: 6266 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1844 AN: 3468

East Asian (EAS) AF: 0.249 AC: 1275 AN: 5124

South Asian (SAS) AF: 0.346 AC: 1660 AN: 4792

European-Finnish (FIN) AF: 0.493 AC: 5173 AN: 10492

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34918 AN: 67882

Other (OTH) AF: 0.474 AC: 999 AN: 2108

Alfa AF: 0.497 Hom.: 70682

Bravo AF: 0.467

Asia WGS AF: 0.313 AC: 1090 AN: 3478

EpiCase AF: 0.499

EpiControl AF: 0.510

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.16
DANN	Benign	0.42
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs1594; hg19: chr2-202025621; COSMIC: COSV58579509; COSMIC: COSV58579509;