rs139688774

Variant names:

• chr7-117479807-G-C
• rs139688774
• ENST00000546407.1:n.166+3999G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-117479807-G-C
• chr7-117479807-G-A
• chr7-117479807-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000446805.2(CFTR):​c.-191+113G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 547,046 control chromosomes in the GnomAD database, including 8 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 0.0048 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: CFTR ENST00000446805.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.817
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-117479807-G-C is Benign according to our data. Variant chr7-117479807-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237853.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0048 (730/152104) while in subpopulation AFR AF = 0.0167 (691/41496). AF 95% confidence interval is 0.0156. There are 7 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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
	CFTR	NM_000492.4	MANE Select	c.-288G>C		upstream_gene	N/A	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000546407.1	TSL:1	n.166+3999G>C		intron	N/A
	CFTR	ENST00000673785.1		c.-406+13976G>C		intron	N/A	ENSP00000501235.1	A0A669KBE8
	CFTR	ENST00000446805.2	TSL:4	c.-191+113G>C		intron	N/A	ENSP00000417012.1	C9J6L5

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 731 AN: 151986 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00336

GnomAD4 exome AF: 0.000517 AC: 204 AN: 394942 Hom.: 1 Cov.: 0 AF XY: 0.000428 AC XY: 89 AN XY: 207922

African (AFR) AF: 0.0144 AC: 163 AN: 11294

American (AMR) AF: 0.000713 AC: 12 AN: 16820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12282

East Asian (EAS) AF: 0.00 AC: 0 AN: 27312

South Asian (SAS) AF: 0.0000227 AC: 1 AN: 43962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24468

Middle Eastern (MID) AF: 0.000576 AC: 1 AN: 1736

European-Non Finnish (NFE) AF: 0.00000427 AC: 1 AN: 234368

Other (OTH) AF: 0.00115 AC: 26 AN: 22700

GnomAD4 genome AF: 0.00480 AC: 730 AN: 152104 Hom.: 7 Cov.: 31 AF XY: 0.00463 AC XY: 344 AN XY: 74342

African (AFR) AF: 0.0167 AC: 691 AN: 41496

American (AMR) AF: 0.00183 AC: 28 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67980

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.00565

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cystic fibrosis (1)
-	-	1	Hereditary pancreatitis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		0.82
PromoterAI		-0.12	Neutral

Splicing

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

Other links and lift over

dbSNP: rs139688774; hg19: chr7-117119861;