7-100995714-C-A

Variant names:

• chr7-100995714-C-A
• rs373887154
• NM_001164462.2:c.5151C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001164462.2(MUC12):​c.5151C>A​(p.His1717Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,536,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Synonymous variant affecting the same amino acid position (i.e. H1717H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MUC12 NM_001164462.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.99
• Publications: 1 publications found

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015694797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC12	NM_001164462.2	c.5151C>A	p.His1717Gln	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.5151C>A	p.His1717Gln	missense_variant	Exon 2 of 12	5	NM_001164462.2	ENSP00000441929.1
MUC12	ENST00000379442.7	c.5580C>A	p.His1860Gln	missense_variant	Exon 5 of 15	5		ENSP00000368755.3

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151352 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000137 AC: 2 AN: 145718 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385406 Hom.: 0 Cov.: 132 AF XY: 0.00 AC XY: 0 AN XY: 683588

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

African (AFR) AF: 0.00 AC: 0 AN: 31578

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078932

Other (OTH) AF: 0.00 AC: 0 AN: 58076

⚠️ 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 AF: 0.00000660 AC: 1 AN: 151466 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74046

African (AFR) AF: 0.00 AC: 0 AN: 40902

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

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

ExAC AF: 0.0000442 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.030
DANN	Benign	0.49
DEOGEN2	Benign	0.0036	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.16	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		-4.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.052
Sift	Benign	0.062	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.027
MutPred		0.12		.;Loss of glycosylation at S1716 (P = 0.1258);
MVP		0.014
ClinPred		0.045	T
GERP RS		-2.4
Varity_R		0.035
gMVP		0.0032
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

Other links and lift over

dbSNP: rs373887154; hg19: chr7-100638995;