NM_000492.4:c.869+11C>T

Variant names:

• chr7-117536684-C-T
• rs1800503
• NM_000492.4:c.869+11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.869+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,604,710 control chromosomes in the GnomAD database, including 4,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (428 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4494 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.615
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-117536684-C-T is Benign according to our data. Variant chr7-117536684-C-T is described in ClinVar as Benign. ClinVar VariationId is 93159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

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.869+11C>T		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.869+11C>T		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.869+11C>T		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.869+11C>T		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11291 AN: 152004 Hom.: 427 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0685

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0517

Gnomad FIN AF: 0.0883

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.0872

GnomAD2 exomes AF: 0.0684 AC: 16890 AN: 246796 AF XY: 0.0699

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0960

Gnomad EAS exome AF: 0.00192

Gnomad FIN exome AF: 0.0936

Gnomad NFE exome AF: 0.0832

Gnomad OTH exome AF: 0.0810

GnomAD4 exome AF: 0.0767 AC: 111477 AN: 1452588 Hom.: 4494 Cov.: 30 AF XY: 0.0770 AC XY: 55688 AN XY: 723034

African (AFR) AF: 0.0642 AC: 2139 AN: 33330

American (AMR) AF: 0.0480 AC: 2142 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 2428 AN: 26006

East Asian (EAS) AF: 0.00263 AC: 104 AN: 39492

South Asian (SAS) AF: 0.0571 AC: 4912 AN: 85950

European-Finnish (FIN) AF: 0.0987 AC: 5044 AN: 51084

Middle Eastern (MID) AF: 0.100 AC: 564 AN: 5632

European-Non Finnish (NFE) AF: 0.0810 AC: 89657 AN: 1106376

Other (OTH) AF: 0.0746 AC: 4487 AN: 60122

GnomAD4 genome AF: 0.0743 AC: 11301 AN: 152122 Hom.: 428 Cov.: 32 AF XY: 0.0739 AC XY: 5496 AN XY: 74384

African (AFR) AF: 0.0629 AC: 2610 AN: 41510

American (AMR) AF: 0.0684 AC: 1046 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5184

South Asian (SAS) AF: 0.0517 AC: 249 AN: 4816

European-Finnish (FIN) AF: 0.0883 AC: 935 AN: 10588

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.0858 AC: 5831 AN: 67956

Other (OTH) AF: 0.0886 AC: 187 AN: 2110

Alfa AF: 0.0832 Hom.: 489

Bravo AF: 0.0722

Asia WGS AF: 0.0360 AC: 127 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Cystic fibrosis (6)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	CFTR-related disorder (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.61
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1800503; hg19: chr7-117176738;