chr7-117587820-A-G

Variant names:

• chr7-117587820-A-G
• rs75789129
• NM_000492.4:c.1666A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000492.4(CFTR):​c.1666A>G​(p.Ile556Val) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,598,980 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I556L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:13
• Conservation: PhyloP100: 3.90
• Publications: 51 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 -17 ACMG points.

• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 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=0.007845759).
• BP6: Variant 7-117587820-A-G is Benign according to our data. Variant chr7-117587820-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00175 (267/152310) while in subpopulation EAS AF = 0.0499 (259/5186). AF 95% confidence interval is 0.0449. There are 6 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.1666A>G	p.Ile556Val	missense	Exon 12 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.1666A>G	p.Ile556Val	missense	Exon 12 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1666A>G	p.Ile556Val	missense	Exon 12 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1666A>G	p.Ile556Val	missense	Exon 12 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00351 AC: 881 AN: 250736 AF XY: 0.00317

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0472

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00122 AC: 1759 AN: 1446670 Hom.: 35 Cov.: 26 AF XY: 0.00115 AC XY: 828 AN XY: 720812

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.0409 AC: 1618 AN: 39522

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85986

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000910 AC: 10 AN: 1098528

Other (OTH) AF: 0.00202 AC: 121 AN: 59808

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0499 AC: 259 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00143 Hom.: 7

Bravo AF: 0.00213

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.0100 AC: 36 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	6	Cystic fibrosis (8)
-	-	3	CFTR-related disorder (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.12
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.30	N
PhyloP100		3.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.44
Sift	Benign	0.54	T
Sift4G	Benign	0.23	T
Polyphen		0.33	B
Vest4		0.85
MVP		0.97
MPC		0.0048
ClinPred		0.070	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.81
Mutation Taster		=61/39	disease causing (ClinVar)

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: rs75789129; hg19: chr7-117227874; COSMIC: COSV105835392; COSMIC: COSV105835392;