rs201716473

Variant names:

• chr7-117602800-A-G
• rs201716473
• NM_000492.4:c.2620-26A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.2620-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,612,290 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (14 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:5 B:10
• Conservation: PhyloP100: 1.54
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• 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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAdExome4 at 14 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2620-26A>G		intron	N/A	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2620-26A>G		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.2620-26A>G		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.2533-26A>G		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00161 AC: 405 AN: 251450 AF XY: 0.00152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00138 AC: 2013 AN: 1459992 Hom.: 14 Cov.: 30 AF XY: 0.00132 AC XY: 962 AN XY: 726468

African (AFR) AF: 0.000179 AC: 6 AN: 33436

American (AMR) AF: 0.0000895 AC: 4 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 666 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86214

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00104 AC: 1151 AN: 1110350

Other (OTH) AF: 0.00260 AC: 157 AN: 60324

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68010

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00425 Hom.: 0

Bravo AF: 0.00121

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	7	Cystic fibrosis (8)
-	3	1	not provided (4)
-	1	-	CFTR-related disorder (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
-	-	1	Hereditary pancreatitis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.62
PhyloP100		1.5
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs201716473; hg19: chr7-117242854;