rs1800086

Variant names:

• chr7-117540282-C-G
• rs1800086
• NM_000492.4:c.1052C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117540282-C-G
• chr7-117540282-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BS2_Supporting

The NM_000492.4(CFTR):​c.1052C>G​(p.Thr351Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,014 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T351I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:13 B:2
• Conservation: PhyloP100: 7.43
• Publications: 12 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_000492.4
• 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.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1052C>G	p.Thr351Ser	missense	Exon 8 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.1052C>G	p.Thr351Ser	missense	Exon 8 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1052C>G	p.Thr351Ser	missense	Exon 8 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1052C>G	p.Thr351Ser	missense	Exon 8 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251162 AF XY: 0.000169

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461732 Hom.: 2 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 727178

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000425 AC: 19 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000150 AC: 167 AN: 1111890

Other (OTH) AF: 0.000613 AC: 37 AN: 60388

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74472

African (AFR) AF: 0.000120 AC: 5 AN: 41548

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	2	Cystic fibrosis (8)
-	5	-	not provided (5)
1	1	-	CFTR-related disorder (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.85
MutPred		0.82		Gain of helix (P = 0.132)
MVP		0.99
MPC		0.0052
ClinPred		0.21	T
GERP RS		5.3
Varity_R		0.80
gMVP		0.83
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800086; hg19: chr7-117180336;