rs213987

Variant names:

• chr7-117621239-C-T
• rs213987
• NM_000492.4:c.3469-6283C>T

Variant summary

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

The NM_000492.4(CFTR):​c.3469-6283C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 151,978 control chromosomes in the GnomAD database, including 19,890 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 0.47 (19890 hom., cov: 33)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• Publications: 9 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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3469-6283C>T		intron_variant	Intron 21 of 26	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.66-4899G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3469-6283C>T		intron_variant	Intron 21 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71343 AN: 151860 Hom.: 19828 Cov.: 33

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.419

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.470 AC: 71471 AN: 151978 Hom.: 19890 Cov.: 33 AF XY: 0.471 AC XY: 34975 AN XY: 74262

African (AFR) AF: 0.789 AC: 32708 AN: 41444

American (AMR) AF: 0.385 AC: 5882 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 867 AN: 3468

East Asian (EAS) AF: 0.332 AC: 1709 AN: 5152

South Asian (SAS) AF: 0.421 AC: 2025 AN: 4812

European-Finnish (FIN) AF: 0.424 AC: 4474 AN: 10558

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22530 AN: 67958

Other (OTH) AF: 0.423 AC: 892 AN: 2110

Alfa AF: 0.368 Hom.: 46865

Bravo AF: 0.481

Asia WGS AF: 0.446 AC: 1555 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.68
PhyloP100		-0.35
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: rs213987; hg19: chr7-117261293;