rs185028612

Variant names:

• chr7-117479634-A-G
• rs185028612
• ENST00000546407.1:n.166+3826A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000446805.2(CFTR):​c.-251A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 204,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: CFTR ENST00000446805.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.10
• 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 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-117479634-A-G is Benign according to our data. Variant chr7-117479634-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 189027.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000446805.2. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000546407.1	TSL:1	n.166+3826A>G		intron	N/A
	CFTR	ENST00000446805.2	TSL:4	c.-251A>G		5_prime_UTR	Exon 3 of 6	ENSP00000417012.1
	CFTR	ENST00000673785.1		c.-406+13803A>G		intron	N/A	ENSP00000501235.1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00192 AC: 101 AN: 52538 Hom.: 1 Cov.: 0 AF XY: 0.00182 AC XY: 50 AN XY: 27450

African (AFR) AF: 0.00 AC: 0 AN: 1678

American (AMR) AF: 0.00 AC: 0 AN: 3536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1276

East Asian (EAS) AF: 0.00 AC: 0 AN: 3386

South Asian (SAS) AF: 0.00 AC: 0 AN: 6608

European-Finnish (FIN) AF: 0.00864 AC: 17 AN: 1968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.00254 AC: 79 AN: 31066

Other (OTH) AF: 0.00178 AC: 5 AN: 2810

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74390

African (AFR) AF: 0.000289 AC: 12 AN: 41526

American (AMR) AF: 0.000458 AC: 7 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00962 AC: 102 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68006

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00408 Hom.: 1

Bravo AF: 0.00116

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Cystic fibrosis (2)
-	-	1	CFTR-related disorder (1)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.47
PhyloP100		-1.1
PromoterAI		-0.020	Neutral

Splicing

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

Other links and lift over

dbSNP: rs185028612; hg19: chr7-117119688;