7-117627653-A-T

Variant names:

• chr7-117627653-A-T
• NM_000492.4:c.3600A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000492.4(CFTR):​c.3600A>T​(p.Lys1200Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.574

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25088096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3600A>T	p.Lys1200Asn	missense_variant	Exon 22 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3600A>T	p.Lys1200Asn	missense_variant	Exon 22 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Uncertain:1

Jan 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1200N variant (also known as c.3600A>T), located in coding exon 22 of the CFTR gene, results from an A to T substitution at nucleotide position 3600. The lysine at codon 1200 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.74	N;.;.;N;.
REVEL	Uncertain	0.37
Sift	Benign	0.16	T;.;.;T;.
Sift4G	Uncertain	0.045	D;.;.;D;.
Polyphen		0.072	B;.;.;.;.
Vest4		0.27
MutPred		0.56		Loss of ubiquitination at K1200 (P = 0.013);.;.;.;.;
MVP		0.99
MPC		0.0038
ClinPred		0.30	T
GERP RS		5.9
Varity_R		0.19
gMVP		0.83

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-117267707;