6-30986573-G-A

Variant names:

• chr6-30986573-G-A
• rs1465364390
• NM_001010909.5:c.398G>A

Variant summary

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

The NM_001010909.5(MUC21):​c.398G>A​(p.Ser133Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S133G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC21 NM_001010909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.48
• Publications: 1 publications found

Genes affected

MUC21 (HGNC:21661): (mucin 21, cell surface associated) This gene encodes a large membrane-bound glycoprotein which 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. These proteins also play a role in intracellular signaling. The encoded protein contains an N-terminal signal sequence, an extracellular mucin domain, a stem domain, a transmembrane domain, and a C-terminal cytoplasmic tail domain. The mucin domain contains O-glycosylation sites and is polymorphic with isoforms containing a variable number of nonidentical proline-, threonine-, and serine-rich tandem repeats of 15 amino acids each. The aberrent expression of this gene is associated with lung adenocarcinoma. [provided by RefSeq, May 2017]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.057054013).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010909.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC21	NM_001010909.5	MANE Select	c.398G>A	p.Ser133Asn	missense	Exon 2 of 3	NP_001010909.2	Q5SSG8-1
	MUC21	NR_130720.3		n.781G>A		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC21	ENST00000376296.3	TSL:1 MANE Select	c.398G>A	p.Ser133Asn	missense	Exon 2 of 3	ENSP00000365473.3	Q5SSG8-1
	MUC21	ENST00000486149.2	TSL:1	c.-965G>A		5_prime_UTR	Exon 2 of 3	ENSP00000457640.1	A0A0C4DGM6

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150512 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

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: 0.0000444

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000351 AC: 5 AN: 1424730 Hom.: 0 Cov.: 171 AF XY: 0.00000282 AC XY: 2 AN XY: 708340

⚠️ 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: 31918

American (AMR) AF: 0.00 AC: 0 AN: 42396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24198

East Asian (EAS) AF: 0.00 AC: 0 AN: 36064

South Asian (SAS) AF: 0.00 AC: 0 AN: 84232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1090666

Other (OTH) AF: 0.0000173 AC: 1 AN: 57966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000154022), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000266 AC: 4 AN: 150614 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73578

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

African (AFR) AF: 0.00 AC: 0 AN: 41018

American (AMR) AF: 0.0000660 AC: 1 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67516

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000100253), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.6
DANN	Benign	0.80
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.5
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.010
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		0.033	B
Vest4		0.030
MutPred		0.19		Loss of phosphorylation at S133 (P = 0.0028)
MVP		0.014
MPC		0.13
ClinPred		0.041	T
GERP RS		0.39
Varity_R		0.18
gMVP		0.022
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: rs1465364390; hg19: chr6-30954350; COSMIC: COSV105303563;