2-201289477-C-T

Variant names:

• chr2-201289477-C-T
• rs17468277
• NM_001127391.3:c.1122G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127391.3(FLACC1):​c.1122G>A​(p.Thr374Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,772 control chromosomes in the GnomAD database, including 11,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (810 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11158 hom.)
• Consequence: FLACC1 NM_001127391.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.573

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-201289477-C-T is Benign according to our data. Variant chr2-201289477-C-T is described in ClinVar as [Benign]. Clinvar id is 402494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.573 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLACC1	NM_001127391.3	c.1122G>A	p.Thr374Thr	synonymous_variant	Exon 14 of 15	ENST00000392257.8	NP_001120863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLACC1	ENST00000392257.8	c.1122G>A	p.Thr374Thr	synonymous_variant	Exon 14 of 15	1	NM_001127391.3	ENSP00000376086.3

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14711 AN: 152154 Hom.: 808 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.0864

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0896 AC: 22515 AN: 251398 Hom.: 1291 AF XY: 0.0891 AC XY: 12111 AN XY: 135868

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0606

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0437

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.117 AC: 171047 AN: 1461500 Hom.: 11158 Cov.: 32 AF XY: 0.115 AC XY: 83650 AN XY: 727064

Gnomad4 AFR exome AF: 0.0577

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.0646

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.0968 AC: 14733 AN: 152272 Hom.: 810 Cov.: 32 AF XY: 0.0932 AC XY: 6942 AN XY: 74454

Gnomad4 AFR AF: 0.0627

Gnomad4 AMR AF: 0.0862

Gnomad4 ASJ AF: 0.0637

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0385

Gnomad4 FIN AF: 0.0979

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.107

Alfa AF: 0.119 Hom.: 1917

Bravo AF: 0.0947

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs17468277; hg19: chr2-202154200; COSMIC: COSV51860617; COSMIC: COSV51860617;