rs1800098

Variant names:

• chr7-117590400-G-C
• rs1800098
• NM_000492.4:c.1727G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-117590400-G-C
• chr7-117590400-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000492.4(CFTR):​c.1727G>C​(p.Gly576Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0068 in 1,602,812 control chromosomes in the GnomAD database, including 52 homozygotes. 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. G576R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (49 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:16 B:9 O:1
• Conservation: PhyloP100: 5.67
• Publications: 79 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 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 GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1727G>C	p.Gly576Ala	missense	Exon 13 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1727G>C	p.Gly576Ala	missense	Exon 13 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1727G>C	p.Gly576Ala	missense	Exon 13 of 27	ENSP00000514471.1
	CFTR	ENST00000889209.1		c.1727G>C	p.Gly576Ala	missense	Exon 13 of 26	ENSP00000559268.1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 758 AN: 151922 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00728

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00586

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00507 AC: 1270 AN: 250304 AF XY: 0.00515

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00538

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00557

GnomAD4 exome AF: 0.00699 AC: 10147 AN: 1450774 Hom.: 49 Cov.: 30 AF XY: 0.00660 AC XY: 4763 AN XY: 721602

African (AFR) AF: 0.00150 AC: 50 AN: 33246

American (AMR) AF: 0.00521 AC: 231 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.000234 AC: 6 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86090

European-Finnish (FIN) AF: 0.00550 AC: 289 AN: 52542

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5694

European-Non Finnish (NFE) AF: 0.00834 AC: 9211 AN: 1104176

Other (OTH) AF: 0.00586 AC: 350 AN: 59678

GnomAD4 genome AF: 0.00499 AC: 758 AN: 152038 Hom.: 3 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74330

African (AFR) AF: 0.00183 AC: 76 AN: 41526

American (AMR) AF: 0.00727 AC: 111 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00586 AC: 62 AN: 10586

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00729 AC: 495 AN: 67872

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00629 Hom.: 2

Bravo AF: 0.00486

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00664 AC: 57

ExAC AF: 0.00513 AC: 623

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00693

EpiControl AF: 0.00718

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	Cystic fibrosis (8)
1	7	-	not provided (9)
-	2	2	CFTR-related disorder (4)
1	1	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
-	1	1	not specified (2)
-	1	-	Chronic sinusitis (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	-	Lung disease, non-specific (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.070	N
PhyloP100		5.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.11	N
REVEL	Pathogenic	0.67
Sift	Benign	0.26	T
Sift4G	Benign	0.14	T
Polyphen		0.91	P
Vest4		0.87
MVP		0.99
MPC		0.0040
ClinPred		0.066	T
GERP RS		4.8
Varity_R		0.49
gMVP		0.90
Mutation Taster		=47/53	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.42		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800098; hg19: chr7-117230454;