rs139379077

Variant names:

• chr7-117602811-C-G
• rs139379077
• NM_000492.4:c.2620-15C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117602811-C-G
• chr7-117602811-C-T

Variant summary

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

The NM_000492.4(CFTR):​c.2620-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,194 control chromosomes in the GnomAD database, including 26 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 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (23 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: -0.425
• Publications: 11 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-117602811-C-G is Benign according to our data. Variant chr7-117602811-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35844.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00189 (2767/1460900) while in subpopulation MID AF = 0.0331 (191/5766). AF 95% confidence interval is 0.0293. There are 23 homozygotes in GnomAdExome4. There are 1494 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2620-15C>G		intron	N/A	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2620-15C>G		intron	N/A	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.2620-15C>G		intron	N/A	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.2530-15C>G		intron	N/A	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152176 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00272 AC: 685 AN: 251464 AF XY: 0.00296

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00189 AC: 2767 AN: 1460900 Hom.: 23 Cov.: 30 AF XY: 0.00206 AC XY: 1494 AN XY: 726818

African (AFR) AF: 0.000927 AC: 31 AN: 33452

American (AMR) AF: 0.00297 AC: 133 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 568 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0331 AC: 191 AN: 5766

European-Non Finnish (NFE) AF: 0.00130 AC: 1445 AN: 1111138

Other (OTH) AF: 0.00437 AC: 264 AN: 60374

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152294 Hom.: 3 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74456

African (AFR) AF: 0.000216 AC: 9 AN: 41572

American (AMR) AF: 0.00484 AC: 74 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00504 Hom.: 2

Bravo AF: 0.00240

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	Cystic fibrosis (7)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	1	-	CFTR-related disorder (1)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.062
DANN	Benign	0.51
PhyloP100		-0.42
Mutation Taster		=99/1	polymorphism

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: rs139379077; hg19: chr7-117242865;