2-201288529-A-C

Variant names:

• chr2-201288529-A-C
• rs700636
• NM_001127391.3:c.*126T>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.*126T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,170,716 control chromosomes in the GnomAD database, including 175,952 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 0.43 (16494 hom., cov: 32)
  • Exomes 𝑓: 0.55 (159458 hom.)
• Consequence: FLACC1 NM_001127391.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 25 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=-0.67).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	NM_001127391.3	c.*126T>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000392257.8	NP_001120863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLACC1	ENST00000392257.8	c.*126T>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_001127391.3	ENSP00000376086.3

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66107 AN: 151968 Hom.: 16492 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.429

GnomAD4 exome AF: 0.551 AC: 561692 AN: 1018630 Hom.: 159458 Cov.: 13 AF XY: 0.547 AC XY: 277809 AN XY: 507744

African (AFR) AF: 0.169 AC: 3940 AN: 23350

American (AMR) AF: 0.424 AC: 11094 AN: 26160

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 7322 AN: 17064

East Asian (EAS) AF: 0.447 AC: 16292 AN: 36454

South Asian (SAS) AF: 0.375 AC: 19324 AN: 51590

European-Finnish (FIN) AF: 0.572 AC: 20915 AN: 36590

Middle Eastern (MID) AF: 0.417 AC: 1921 AN: 4612

European-Non Finnish (NFE) AF: 0.588 AC: 458033 AN: 778534

Other (OTH) AF: 0.516 AC: 22851 AN: 44276

GnomAD4 genome AF: 0.435 AC: 66127 AN: 152086 Hom.: 16494 Cov.: 32 AF XY: 0.432 AC XY: 32142 AN XY: 74354

African (AFR) AF: 0.184 AC: 7641 AN: 41498

American (AMR) AF: 0.409 AC: 6251 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1497 AN: 3468

East Asian (EAS) AF: 0.480 AC: 2482 AN: 5166

South Asian (SAS) AF: 0.373 AC: 1798 AN: 4826

European-Finnish (FIN) AF: 0.571 AC: 6031 AN: 10562

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38810 AN: 67978

Other (OTH) AF: 0.427 AC: 900 AN: 2106

Alfa AF: 0.514 Hom.: 35977

Bravo AF: 0.415

Asia WGS AF: 0.410 AC: 1427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	4.7
DANN	Benign	0.82
PhyloP100		0.24
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: rs700636; hg19: chr2-202153252; COSMIC: COSV51861850; COSMIC: COSV51861850;