2-201343270-T-C

Variant names:

• chr2-201343270-T-C
• rs7577057
• NM_001127391.3:c.463-839A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127391.3(FLACC1):​c.463-839A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 152,132 control chromosomes in the GnomAD database, including 14,168 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 0.42 (14168 hom., cov: 33)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.555
• Publications: 8 publications found

Genes affected

FLACC1 (HGNC:14439): (flagellum associated containing coiled-coil domains 1) Predicted to be located in cytoplasmic vesicle and sperm flagellum. Predicted to be active in cytoplasm; outer dense fiber; and sperm fibrous sheath. [provided by Alliance of Genome Resources, Apr 2022]

CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	NM_001127391.3	c.463-839A>G		intron_variant	Intron 6 of 14	ENST00000392257.8	NP_001120863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLACC1	ENST00000392257.8	c.463-839A>G		intron_variant	Intron 6 of 14	1	NM_001127391.3	ENSP00000376086.3

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64011 AN: 152014 Hom.: 14175 Cov.: 33

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.421 AC: 64008 AN: 152132 Hom.: 14168 Cov.: 33 AF XY: 0.423 AC XY: 31427 AN XY: 74368

African (AFR) AF: 0.283 AC: 11744 AN: 41514

American (AMR) AF: 0.354 AC: 5409 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1492 AN: 3472

East Asian (EAS) AF: 0.447 AC: 2315 AN: 5176

South Asian (SAS) AF: 0.539 AC: 2601 AN: 4826

European-Finnish (FIN) AF: 0.534 AC: 5647 AN: 10566

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33474 AN: 67964

Other (OTH) AF: 0.387 AC: 819 AN: 2114

Alfa AF: 0.465 Hom.: 52079

Bravo AF: 0.401

Asia WGS AF: 0.481 AC: 1675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.72
DANN	Benign	0.51
PhyloP100		-0.56
Mutation Taster		=100/0	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: rs7577057; hg19: chr2-202207993;