2-201288355-T-G

Variant names:

• chr2-201288355-T-G
• rs1035142
• NM_001127391.3:c.*300A>C

Variant summary

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

The NM_001127391.3(FLACC1):​c.*300A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 236,020 control chromosomes in the GnomAD database, including 38,242 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 0.54 (23054 hom., cov: 31)
  • Exomes 𝑓: 0.59 (15188 hom.)
• Consequence: FLACC1 NM_001127391.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.238
• Publications: 42 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 (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127391.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	NM_001127391.3	MANE Select	c.*300A>C		3_prime_UTR	Exon 15 of 15	NP_001120863.1
	FLACC1	NR_110620.2		n.2146A>C		non_coding_transcript_exon	Exon 14 of 14
	FLACC1	NM_139163.4		c.*300A>C		3_prime_UTR	Exon 15 of 15	NP_631902.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	ENST00000392257.8	TSL:1 MANE Select	c.*300A>C		3_prime_UTR	Exon 15 of 15	ENSP00000376086.3
	FLACC1	ENST00000286190.9	TSL:1	c.*300A>C		3_prime_UTR	Exon 14 of 14	ENSP00000286190.5
	CASP8	ENST00000696069.1		c.1259+3038T>G		intron	N/A	ENSP00000512371.1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81989 AN: 151846 Hom.: 23033 Cov.: 31

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.531

GnomAD4 exome AF: 0.593 AC: 49861 AN: 84056 Hom.: 15188 Cov.: 3 AF XY: 0.595 AC XY: 25469 AN XY: 42792

African (AFR) AF: 0.398 AC: 1280 AN: 3216

American (AMR) AF: 0.450 AC: 1716 AN: 3816

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1802 AN: 3502

East Asian (EAS) AF: 0.656 AC: 4338 AN: 6614

South Asian (SAS) AF: 0.631 AC: 1436 AN: 2276

European-Finnish (FIN) AF: 0.610 AC: 2518 AN: 4126

Middle Eastern (MID) AF: 0.597 AC: 264 AN: 442

European-Non Finnish (NFE) AF: 0.611 AC: 33288 AN: 54444

Other (OTH) AF: 0.573 AC: 3219 AN: 5620

GnomAD4 genome AF: 0.540 AC: 82053 AN: 151964 Hom.: 23054 Cov.: 31 AF XY: 0.541 AC XY: 40178 AN XY: 74280

African (AFR) AF: 0.395 AC: 16372 AN: 41420

American (AMR) AF: 0.459 AC: 7014 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1781 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3524 AN: 5162

South Asian (SAS) AF: 0.644 AC: 3107 AN: 4824

European-Finnish (FIN) AF: 0.611 AC: 6442 AN: 10538

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41875 AN: 67970

Other (OTH) AF: 0.528 AC: 1111 AN: 2106

Alfa AF: 0.588 Hom.: 88690

Bravo AF: 0.523

Asia WGS AF: 0.641 AC: 2231 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.0
DANN	Benign	0.59
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: rs1035142; hg19: chr2-202153078;