7-100999174-G-A

Variant names:

• chr7-100999174-G-A
• rs200303708
• NM_001164462.2:c.8611G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001164462.2(MUC12):​c.8611G>A​(p.Ala2871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 79,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC12 NM_001164462.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.53

Genes affected

MUC12 (HGNC:7510): (mucin 12, cell surface associated) This gene encodes an integral membrane glycoprotein that is a member of the mucin family. Mucins are O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces and have been implicated in epithelial renewal and differentiation. These glycoproteins also play a role in intracellular signaling. This protein is expressed on the apical membrane surface of epithelial cells that line the mucosal surfaces of many different tissues including the colon, pancreas, prostate, and uterus. The expression of this gene is downregulated in colorectal cancer tissue. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025514364).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC12	NM_001164462.2	c.8611G>A	p.Ala2871Thr	missense_variant	Exon 2 of 12	ENST00000536621.6	NP_001157934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC12	ENST00000536621.6	c.8611G>A	p.Ala2871Thr	missense_variant	Exon 2 of 12	5	NM_001164462.2	ENSP00000441929.1
MUC12	ENST00000379442.7	c.9040G>A	p.Ala3014Thr	missense_variant	Exon 5 of 15	5		ENSP00000368755.3

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 2128 AN: 79840 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.00338

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00626

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0146

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0299

GnomAD2 exomes AF: 0.0235 AC: 1608 AN: 68304 AF XY: 0.0227

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.0212

Gnomad ASJ exome AF: 0.00629

Gnomad EAS exome AF: 0.0376

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0211

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0200 AC: 10366 AN: 519142 Hom.: 0 Cov.: 56 AF XY: 0.0191 AC XY: 5009 AN XY: 262508

Gnomad4 AFR exome AF: 0.0300 AC: 511 AN: 17016

Gnomad4 AMR exome AF: 0.0132 AC: 315 AN: 23888

Gnomad4 ASJ exome AF: 0.00131 AC: 17 AN: 12960

Gnomad4 EAS exome AF: 0.0415 AC: 1048 AN: 25270

Gnomad4 SAS exome AF: 0.0147 AC: 571 AN: 38916

Gnomad4 FIN exome AF: 0.00266 AC: 52 AN: 19524

Gnomad4 NFE exome AF: 0.0209 AC: 7382 AN: 352952

Gnomad4 Remaining exome AF: 0.0165 AC: 428 AN: 25910

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

GnomAD4 genome AF: 0.0267 AC: 2135 AN: 79908 Hom.: 0 Cov.: 30 AF XY: 0.0278 AC XY: 1049 AN XY: 37692

Gnomad4 AFR AF: 0.0359 AC: 0.0359344 AN: 0.0359344

Gnomad4 AMR AF: 0.0175 AC: 0.017494 AN: 0.017494

Gnomad4 ASJ AF: 0.00626 AC: 0.00625652 AN: 0.00625652

Gnomad4 EAS AF: 0.0581 AC: 0.0580728 AN: 0.0580728

Gnomad4 SAS AF: 0.0498 AC: 0.0498221 AN: 0.0498221

Gnomad4 FIN AF: 0.0222 AC: 0.0222167 AN: 0.0222167

Gnomad4 NFE AF: 0.0202 AC: 0.0201788 AN: 0.0201788

Gnomad4 OTH AF: 0.0323 AC: 0.032316 AN: 0.032316

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

Alfa AF: 0.0584 Hom.: 0

ExAC AF: 0.157 AC: 2384

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

James Howe Lab, University of Iowa Hospital and Clinics

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.93
DEOGEN2	Benign	0.0032	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.032
Sift	Benign	0.053	T;D
Sift4G	Benign	0.29	T;T
Vest4		0.011
ClinPred		0.0062	T
GERP RS		0.47
Varity_R		0.089
gMVP		0.013
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs200303708; hg19: chr7-100642455; COSMIC: COSV65197298;