chr2-201145378-C-A

Position:

• chr2-201145378-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003879.7(CFLAR):​c.607C>A​(p.Leu203Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,597,212 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.021 (114 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (109 hom.)
• Consequence: CFLAR NM_003879.7 missense, splice_region
• Scores: Splicing: ADA: 0.00005668
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.264

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014910996).
• BP6: Variant 2-201145378-C-A is Benign according to our data. Variant chr2-201145378-C-A is described in ClinVar as [Benign]. Clinvar id is 783347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFLAR	NM_003879.7	c.607C>A	p.Leu203Ile	missense_variant, splice_region_variant	6/10	ENST00000309955.8	NP_003870.4
CFLAR-AS1	NR_040030.1	n.884+3356G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFLAR	ENST00000309955.8	c.607C>A	p.Leu203Ile	missense_variant, splice_region_variant	6/10	1	NM_003879.7	ENSP00000312455	P2
CFLAR-AS1	ENST00000415011.6	n.915+3356G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3120 AN: 152140 Hom.: 114 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00529 AC: 1325 AN: 250390 Hom.: 48 AF XY: 0.00400 AC XY: 542 AN XY: 135352

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00217 AC: 3131 AN: 1444954 Hom.: 109 Cov.: 26 AF XY: 0.00191 AC XY: 1377 AN XY: 719786

Gnomad4 AFR exome AF: 0.0728

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.00438

GnomAD4 genome AF: 0.0205 AC: 3123 AN: 152258 Hom.: 114 Cov.: 32 AF XY: 0.0191 AC XY: 1420 AN XY: 74448

Gnomad4 AFR AF: 0.0706

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00493 Hom.: 36

Bravo AF: 0.0226

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0688 AC: 303

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00647 AC: 786

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T;.;.;T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.77	.;T;T;T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;M;M;M;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.20	N;N;N;N;N;.;.
REVEL	Benign	0.072
Sift	Benign	0.14	T;T;T;T;T;.;.
Sift4G	Benign	0.10	T;T;T;T;T;T;T
Polyphen		0.18	B;.;B;B;B;.;B
Vest4		0.20
MVP		0.51
MPC		0.34
ClinPred		0.022	T
GERP RS		1.6
Varity_R		0.12
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.030		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: rs13424615; hg19: chr2-202010101; COSMIC: COSV100010120; COSMIC: COSV100010120;