2-201136003-A-C

Variant names:

• chr2-201136003-A-C
• NM_003879.7:c.419A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003879.7(CFLAR):​c.419A>C​(p.Lys140Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFLAR NM_003879.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.419A>C	p.Lys140Thr	missense_variant	Exon 4 of 10	ENST00000309955.8	NP_003870.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.419A>C	p.Lys140Thr	missense_variant	Exon 4 of 10	1	NM_003879.7	ENSP00000312455.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.419A>C (p.K140T) alteration is located in exon 4 (coding exon 3) of the CFLAR gene. This alteration results from a A to C substitution at nucleotide position 419, causing the lysine (K) at amino acid position 140 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.;.;D;.;.;D;D;.;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.2	M;.;M;M;M;.;M;M;M;.;.;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D;D;D;D;.;.;.;D;.
Vest4		0.57
MutPred		0.73		Loss of ubiquitination at K140 (P = 0.0255);.;Loss of ubiquitination at K140 (P = 0.0255);Loss of ubiquitination at K140 (P = 0.0255);Loss of ubiquitination at K140 (P = 0.0255);Loss of ubiquitination at K140 (P = 0.0255);Loss of ubiquitination at K140 (P = 0.0255);Loss of ubiquitination at K140 (P = 0.0255);Loss of ubiquitination at K140 (P = 0.0255);.;.;.;.;.;
MVP		0.93
MPC		2.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.71
Mutation Taster		=44/56	disease causing

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

hg19: chr2-202000726;