chr11-1017466-T-A

Position:

• chr11-1017466-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_005961.3(MUC6):​c.5335A>T​(p.Arg1779Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,134,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.037 (0 hom., cov: 119)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC6 NM_005961.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -2.47

Genes affected

MUC6 (HGNC:7517): (mucin 6, oligomeric mucus/gel-forming) This gene encodes a member of the mucin protein family. Mucins are high molecular weight glycoproteins produced by many epithelial tissues. The protein encoded by this gene is secreted and forms an insoluble mucous barrier that protects the gut lumen. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC6	NM_005961.3	c.5335A>T	p.Arg1779Ter	stop_gained	31/33	ENST00000421673.7	NP_005952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC6	ENST00000421673.7	c.5335A>T	p.Arg1779Ter	stop_gained	31/33	5	NM_005961.3	ENSP00000406861	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3720 AN: 101610 Hom.: 0 Cov.: 119 FAILED QC

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.0498

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0290

Gnomad EAS AF: 0.0244

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.0514

Gnomad MID AF: 0.0549

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0388

GnomAD4 exome AF: 0.00123 AC: 1391 AN: 1134348 Hom.: 0 Cov.: 306 AF XY: 0.00130 AC XY: 718 AN XY: 551408

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00395

Gnomad4 ASJ exome AF: 0.00120

Gnomad4 EAS exome AF: 0.00129

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.00780

Gnomad4 NFE exome AF: 0.000905

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0365 AC: 3713 AN: 101694 Hom.: 0 Cov.: 119 AF XY: 0.0383 AC XY: 1896 AN XY: 49502

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.0472

Gnomad4 ASJ AF: 0.0290

Gnomad4 EAS AF: 0.0241

Gnomad4 SAS AF: 0.0368

Gnomad4 FIN AF: 0.0514

Gnomad4 NFE AF: 0.0389

Gnomad4 OTH AF: 0.0377

ExAC AF: 0.0307 AC: 3595

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Small cell lung carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Arun Kumar Laboratory, Indian Institute of Science

Jun 15, 2021

- -

Lung cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Arun Kumar Laboratory, Indian Institute of Science

Jun 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Benign	0.97
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.036	N
MutationTaster	Benign	1.0	A
Vest4		0.11
GERP RS		0.018

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

LitVar

Other links and lift over

dbSNP: rs201054567; hg19: chr11-1017466;