rs397508232

Positions:

• chr7-117559705-C-CTACCCAAATTA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000492.4(CFTR):​c.1584+53_1584+63dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,251,778 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.959

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 7-117559705-C-CTACCCAAATTA is Benign according to our data. Variant chr7-117559705-C-CTACCCAAATTA is described in ClinVar as [Likely_benign]. Clinvar id is 439056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1584+53_1584+63dup		intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.221+1027_221+1028insTAATTTGGGTA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1584+53_1584+63dup		intron_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 479 AN: 152122 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000662 AC: 154 AN: 232686 Hom.: 0 AF XY: 0.000531 AC XY: 67 AN XY: 126264

Gnomad AFR exome AF: 0.00819

Gnomad AMR exome AF: 0.000604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000581

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.000337 AC: 370 AN: 1099538 Hom.: 1 Cov.: 14 AF XY: 0.000295 AC XY: 166 AN XY: 563352

Gnomad4 AFR exome AF: 0.00962

Gnomad4 AMR exome AF: 0.000880

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000596

Gnomad4 OTH exome AF: 0.000577

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152240 Hom.: 5 Cov.: 32 AF XY: 0.00296 AC XY: 220 AN XY: 74450

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00196 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 25, 2018

Variant summary: CFTR c.1584+53_1584+63dup11 is located at a deep intronic position not widely known to affect splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00088 in 259470 control chromosomes, predominantly within the African subpopulation in the gnomAD database at a frequency of 0.0086, including 1 homozygote. The observed variant frequency within African control individuals is approximately 1.5-fold above the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk phenotype (0.0063), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1584+53_1584+63dup11 has been reported in the literature without evidence for pathogenicity, thus these reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Cystic fibrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 14, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397508232; hg19: chr7-117199759;