2-201140405-A-C

Variant names:

• chr2-201140405-A-C
• rs768478784
• NM_003879.7:c.572A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003879.7(CFLAR):​c.572A>C​(p.Gln191Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFLAR NM_003879.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0140
• Publications: 0 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]

CFLAR-AS1 (HGNC:14437): (CFLAR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021782279).
• BP6: Variant 2-201140405-A-C is Benign according to our data. Variant chr2-201140405-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2619452.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.572A>C	p.Gln191Pro	missense_variant	Exon 5 of 10	ENST00000309955.8	NP_003870.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.572A>C	p.Gln191Pro	missense_variant	Exon 5 of 10	1	NM_003879.7	ENSP00000312455.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458298 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725582

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 43552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39314

South Asian (SAS) AF: 0.00 AC: 0 AN: 85464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111170

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 19, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.7
DANN	Benign	0.57
DEOGEN2	Benign	0.053	T;.;.;.;.;T;.;.;T;T;.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.63	.;T;.;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-2.6	N;.;N;N;N;N;N;N;.;.;.;.;.
PhyloP100		0.014
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.1	N;N;N;N;N;N;N;N;.;.;.;.;.
REVEL	Benign	0.020
Sift	Benign	1.0	T;T;T;T;T;T;T;T;.;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;B;B;B;B;.;.;.;B;.
Vest4		0.13
MutPred		0.47		Loss of MoRF binding (P = 0.0313);.;Loss of MoRF binding (P = 0.0313);Loss of MoRF binding (P = 0.0313);Loss of MoRF binding (P = 0.0313);Loss of MoRF binding (P = 0.0313);Loss of MoRF binding (P = 0.0313);Loss of MoRF binding (P = 0.0313);.;.;.;.;.;
MVP		0.20
MPC		0.37
ClinPred		0.034	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.51
Mutation Taster		=87/13	polymorphism

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: rs768478784; hg19: chr2-202005128;