rs80034486

Variant names:

• chr7-117652877-C-G
• rs80034486
• NM_000492.4:c.3909C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117652877-C-G
• chr7-117652877-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3909C>G​(p.Asn1303Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,598,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1303H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic practice guideline P:45 U:1 O:2
• Conservation: PhyloP100: 0.670
• Publications: 574 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117652875-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7218.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 7-117652877-C-G is Pathogenic according to our data. Variant chr7-117652877-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7136.Status of the report is practice_guideline, 4 stars.

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.3909C>G	p.Asn1303Lys	missense	Exon 24 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3909C>G	p.Asn1303Lys	missense	Exon 24 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3903C>G	p.Asn1301Lys	missense	Exon 24 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3822C>G	p.Asn1274Lys	missense	Exon 23 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000144 AC: 36 AN: 249546 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000158 AC: 228 AN: 1445874 Hom.: 0 Cov.: 27 AF XY: 0.000179 AC XY: 129 AN XY: 720082

African (AFR) AF: 0.00 AC: 0 AN: 33152

American (AMR) AF: 0.000112 AC: 5 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 13 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000586 AC: 5 AN: 85326

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53338

Middle Eastern (MID) AF: 0.000589 AC: 3 AN: 5092

European-Non Finnish (NFE) AF: 0.000172 AC: 189 AN: 1099168

Other (OTH) AF: 0.000201 AC: 12 AN: 59786

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74420

African (AFR) AF: 0.0000241 AC: 1 AN: 41540

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67980

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
21	1	-	Cystic fibrosis (24)
15	-	-	not provided (15)
3	-	-	CFTR-related disorder (3)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis diagnostic test (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Hereditary pancreatitis (1)
1	-	-	Spermatogenic failure, Y-linked, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		0.67
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Gain of ubiquitination at N1303 (P = 0.03)
MVP		0.99
MPC		0.016
ClinPred		0.86	D
GERP RS		1.3
PromoterAI		-0.010	Neutral
Varity_R		0.99
gMVP		0.97
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs80034486; hg19: chr7-117292931;