chr11-1018419-G-T

Variant names:

• chr11-1018419-G-T
• rs148581741
• NM_005961.3:c.4382C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005961.3(MUC6):​c.4382C>A​(p.Thr1461Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. T1461I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 55)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC6 NM_005961.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.16
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044368178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC6	NM_005961.3	c.4382C>A	p.Thr1461Lys	missense_variant	Exon 31 of 33	ENST00000421673.7	NP_005952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC6	ENST00000421673.7	c.4382C>A	p.Thr1461Lys	missense_variant	Exon 31 of 33	5	NM_005961.3	ENSP00000406861.2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151248 Hom.: 0 Cov.: 55

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000116 AC: 1 AN: 86506 AF XY: 0.0000228

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000154 AC: 2 AN: 1298282 Hom.: 0 Cov.: 211 AF XY: 0.00000155 AC XY: 1 AN XY: 647086

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000671 AC: 2 AN: 29808

American (AMR) AF: 0.00 AC: 0 AN: 41272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24026

East Asian (EAS) AF: 0.00 AC: 0 AN: 37828

South Asian (SAS) AF: 0.00 AC: 0 AN: 79580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 973864

Other (OTH) AF: 0.00 AC: 0 AN: 54792

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000264 AC: 4 AN: 151364 Hom.: 0 Cov.: 55 AF XY: 0.0000270 AC XY: 2 AN XY: 73992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000971 AC: 4 AN: 41214

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67746

Other (OTH) AF: 0.00 AC: 0 AN: 2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000702897), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.022
DANN	Benign	0.71
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0021	N
M_CAP	Benign	0.00068	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-6.2
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.0060
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.032	D
Vest4		0.065
ClinPred		0.040	T
GERP RS		-4.7
Varity_R		0.070
gMVP		0.25
Mutation Taster		=99/1	polymorphism

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: rs148581741; hg19: chr11-1018419; COSMIC: COSV70139336; COSMIC: COSV70139336;