chr2-201160763-G-A

Variant names:

• chr2-201160763-G-A
• rs151223777
• NM_003879.7:c.1125G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003879.7(CFLAR):​c.1125G>A​(p.Val375Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,614,100 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (67 hom.)
• Consequence: CFLAR NM_003879.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.317
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-201160763-G-A is Benign according to our data. Variant chr2-201160763-G-A is described in ClinVar as [Benign]. Clinvar id is 773850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.317 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00201 (2934/1461840) while in subpopulation AMR AF = 0.0395 (1766/44718). AF 95% confidence interval is 0.038. There are 67 homozygotes in GnomAdExome4. There are 1257 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.1125G>A	p.Val375Val	synonymous_variant	Exon 9 of 10	ENST00000309955.8	NP_003870.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.1125G>A	p.Val375Val	synonymous_variant	Exon 9 of 10	1	NM_003879.7	ENSP00000312455.2

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152142 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00723 AC: 1817 AN: 251352 AF XY: 0.00534

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00892

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00201 AC: 2934 AN: 1461840 Hom.: 67 Cov.: 35 AF XY: 0.00173 AC XY: 1257 AN XY: 727238

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.0395 AC: 1766 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0187 AC: 742 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000294 AC: 327 AN: 1111974

Other (OTH) AF: 0.00129 AC: 78 AN: 60394

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152260 Hom.: 8 Cov.: 31 AF XY: 0.00210 AC XY: 156 AN XY: 74444

African (AFR) AF: 0.000963 AC: 40 AN: 41540

American (AMR) AF: 0.0135 AC: 206 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00925 AC: 48 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.00403

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.9
DANN	Benign	0.83
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs151223777; hg19: chr2-202025486;