rs2349073

chr2-201322263-C-Achr2-201322263-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127391.3(FLACC1):c.675+8207G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 141,944 control chromosomes in the GnomAD database, including 38,519 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 0.75 (38519 hom., cov: 24)
• Consequence: FLACC1 NM_001127391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLACC1	NM_001127391.3	c.675+8207G>T		intron_variant		ENST00000392257.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLACC1	ENST00000392257.8	c.675+8207G>T		intron_variant		1	NM_001127391.3	P1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 106725 AN: 141856 Hom.: 38495 Cov.: 24

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.718

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

GnomAD4 genome AF: 0.752 AC: 106786 AN: 141944 Hom.: 38519 Cov.: 24 AF XY: 0.750 AC XY: 51695 AN XY: 68888

Gnomad4 AFR AF: 0.804

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.669

Gnomad4 EAS AF: 0.734

Gnomad4 SAS AF: 0.843

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.748

Gnomad4 OTH AF: 0.718

Alfa AF: 0.629 Hom.: 1154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.075
Dann	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs2349073; hg19: chr2-202186986;