rs147945812

Variant names:

• chr7-117610687-C-T
• rs147945812
• NM_000492.4:c.3139+18C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.3139+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,611,608 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.546
• Publications: 3 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-117610687-C-T is Benign according to our data. Variant chr7-117610687-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3139+18C>T		intron	N/A	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+5542G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3139+18C>T		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3139+18C>T		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3052+18C>T		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 151934 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00474

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00131 AC: 329 AN: 250194 AF XY: 0.00145

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00147 AC: 2139 AN: 1459556 Hom.: 3 Cov.: 31 AF XY: 0.00147 AC XY: 1064 AN XY: 726152

African (AFR) AF: 0.000120 AC: 4 AN: 33392

American (AMR) AF: 0.000134 AC: 6 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 79 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86182

European-Finnish (FIN) AF: 0.00302 AC: 161 AN: 53310

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5746

European-Non Finnish (NFE) AF: 0.00152 AC: 1684 AN: 1110366

Other (OTH) AF: 0.00124 AC: 75 AN: 60272

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152052 Hom.: 1 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74310

African (AFR) AF: 0.000313 AC: 13 AN: 41502

American (AMR) AF: 0.0000656 AC: 1 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00474 AC: 50 AN: 10542

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 67980

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000922

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Cystic fibrosis (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.46
PhyloP100		-0.55
Mutation Taster		=100/0	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: rs147945812; hg19: chr7-117250741;