rs1800097

Variant names:

• chr7-117590357-G-A
• rs1800097
• NM_000492.4:c.1684G>A
• CFTR p.Val562Ile

Your query was ambiguous. Multiple possible variants found:

• chr7-117590357-G-A
• chr7-117590357-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4 BP6

The NM_000492.4(CFTR):​c.1684G>A​(p.Val562Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,602,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V562A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:5
• Conservation: PhyloP100: 7.38
• Publications: 32 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), Laboratory for Molecular Medicine, Myriad Women's Health
• 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 1 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31232405).
• BP6: Variant 7-117590357-G-A is Benign according to our data. Variant chr7-117590357-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35830.

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.1684G>A	p.Val562Ile	missense	Exon 13 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.1684G>A	p.Val562Ile	missense	Exon 13 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1684G>A	p.Val562Ile	missense	Exon 13 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889209.1		c.1684G>A	p.Val562Ile	missense	Exon 13 of 26	ENSP00000559268.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000140 AC: 35 AN: 250340 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000165 AC: 239 AN: 1450402 Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 120 AN XY: 721284

African (AFR) AF: 0.000211 AC: 7 AN: 33222

American (AMR) AF: 0.000383 AC: 17 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52510

Middle Eastern (MID) AF: 0.000880 AC: 5 AN: 5682

European-Non Finnish (NFE) AF: 0.000165 AC: 182 AN: 1103924

Other (OTH) AF: 0.000436 AC: 26 AN: 59628

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74384

African (AFR) AF: 0.0000963 AC: 4 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67876

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000287

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	3	Cystic fibrosis (7)
-	3	1	not provided (4)
-	2	-	CFTR-related disorder (2)
-	1	-	Hereditary pancreatitis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.047
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	-0.15	N
PhyloP100		7.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.64
Sift	Benign	0.042	D
Sift4G	Benign	0.071	T
Varity_R		0.45
gMVP		0.84
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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

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

Other links and lift over

dbSNP: rs1800097;

hg19: chr7-117230411;