rs397508232

Variant names:

• chr7-117559705-C-CTACCCAAATTA
• rs397508232
• NM_000492.4:c.1584+53_1584+63dupCCCAAATTATA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000492.4(CFTR):​c.1584+53_1584+63dupCCCAAATTATA 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 1 publications found

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:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 439056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. 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
	CFTR	NM_000492.4	MANE Select	c.1584+53_1584+63dupCCCAAATTATA		intron	N/A	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1017_221+1027dupTAATTTGGGTA		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1584+53_1584+63dupCCCAAATTATA		intron	N/A	ENSP00000003084.6
	CFTR	ENST00000699596.1		c.*26_*36dupCCCAAATTATA		3_prime_UTR	Exon 11 of 11	ENSP00000514465.1
	CFTR	ENST00000699597.1		c.*195_*205dupCCCAAATTATA		3_prime_UTR	Exon 11 of 11	ENSP00000514466.1

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

GnomAD2 exomes AF: 0.000662 AC: 154 AN: 232686 AF XY: 0.000531

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 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

African (AFR) AF: 0.00962 AC: 252 AN: 26198

American (AMR) AF: 0.000880 AC: 38 AN: 43178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 37910

South Asian (SAS) AF: 0.0000384 AC: 3 AN: 78166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49310

Middle Eastern (MID) AF: 0.000459 AC: 2 AN: 4362

European-Non Finnish (NFE) AF: 0.0000596 AC: 47 AN: 788020

Other (OTH) AF: 0.000577 AC: 28 AN: 48502

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

African (AFR) AF: 0.0109 AC: 453 AN: 41554

American (AMR) AF: 0.00105 AC: 16 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

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

Oct 25, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Sep 28, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397508232; hg19: chr7-117199759;