11-26565803-G-C

Position:

• chr11-26565803-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001135091.2(MUC15):​c.137C>G​(p.Ser46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,611,388 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (22 hom.)
• Consequence: MUC15 NM_001135091.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0450

Genes affected

MUC15 (HGNC:14956): (mucin 15, cell surface associated) Predicted to be located in Golgi lumen and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANO3 (HGNC:14004): (anoctamin 3) The protein encoded by this gene belongs to the TMEM16 family of predicted membrane proteins, that are also known as anoctamins. While little is known about the function of this gene, mutations in this gene have been associated with some cases of autosomal dominant craniocervical dystonia. Cells from individuals with a mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling. Studies in rat show that the rat ortholog of this protein interacts with, and modulates the activity of a sodium-activated potassium channel. Deletion of this gene caused increased pain sensitivity in the rat model system. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045607984).
• BP6: Variant 11-26565803-G-C is Benign according to our data. Variant chr11-26565803-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 235242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00941 (1415/150294) while in subpopulation AFR AF= 0.032 (1324/41326). AF 95% confidence interval is 0.0306. There are 26 homozygotes in gnomad4. There are 681 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC15	NM_001135091.2	c.137C>G	p.Ser46Trp	missense_variant	3/5	ENST00000529533.6	NP_001128563.1
ANO3	NM_031418.4	c.1447+6024G>C		intron_variant		ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC15	ENST00000529533.6	c.137C>G	p.Ser46Trp	missense_variant	3/5	1	NM_001135091.2	ENSP00000431983.1
ANO3	ENST00000256737.8	c.1447+6024G>C		intron_variant		1	NM_031418.4	ENSP00000256737.3

Frequencies

GnomAD3 genomes AF: 0.00940 AC: 1412 AN: 150176 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00444

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00776

GnomAD3 exomes AF: 0.00232 AC: 580 AN: 250414 Hom.: 5 AF XY: 0.00162 AC XY: 219 AN XY: 135350

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000960 AC: 1402 AN: 1461094 Hom.: 22 Cov.: 34 AF XY: 0.000805 AC XY: 585 AN XY: 726846

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00941 AC: 1415 AN: 150294 Hom.: 26 Cov.: 33 AF XY: 0.00926 AC XY: 681 AN XY: 73552

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.00443

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.00768

Alfa AF: 0.000173 Hom.: 1

Bravo AF: 0.0106

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 10, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.3
DANN	Benign	0.85
DEOGEN2	Benign	0.030	T;T;T;T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.79	T;T;T;.;.;T
MetaRNN	Benign	0.0046	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;N;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.46	N;N;N;N;N;.
REVEL	Benign	0.062
Sift	Benign	0.16	T;T;T;T;T;.
Sift4G	Benign	0.16	T;T;T;T;T;.
Polyphen		0.95	.;.;P;.;.;.
Vest4		0.30
MVP		0.048
MPC		0.038
ClinPred		0.0089	T
GERP RS		0.86
Varity_R		0.031
gMVP		0.13

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: rs293979; hg19: chr11-26587350;