rs397508382

Variant names:

• chr7-117592655-A-C
• rs397508382
• NM_000492.4:c.2488A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-117592655-A-C
• chr7-117592655-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000492.4(CFTR):​c.2488A>C​(p.Lys830Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000719 in 1,391,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K830R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.5265
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.66
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2488A>C	p.Lys830Gln	missense_variant, splice_region_variant	Exon 14 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2488A>C	p.Lys830Gln	missense_variant, splice_region_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391076 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687608

African (AFR) AF: 0.00 AC: 0 AN: 30872

American (AMR) AF: 0.00 AC: 0 AN: 30580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.00 AC: 0 AN: 70582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5464

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084346

Other (OTH) AF: 0.00 AC: 0 AN: 57398

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		6.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.66	N;.;N;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0080	D;.;D;.
Sift4G	Uncertain	0.010	D;.;D;.
Polyphen		0.47	P;.;.;.
Vest4		0.42
MutPred		0.48		Loss of ubiquitination at K830 (P = 0.0051);.;.;.;
MVP		0.97
MPC		0.0041
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.33
gMVP		0.56
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.54
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: rs397508382; hg19: chr7-117232709;