1-84937887-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_153259.4(MCOLN2):c.1213-10T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,142 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: MCOLN2 NM_153259.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001299
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.318

Genes affected

MCOLN2 (HGNC:13357): (mucolipin TRP cation channel 2) Mucolipins constitute a family of cation channel proteins with homology to the transient receptor potential superfamily. In mammals, the mucolipin family includes 3 members, MCOLN1 (MIM 605248), MCOLN2, and MCOLN3 (MIM 607400), that exhibit a common 6-membrane-spanning topology. Homologs of mammalian mucolipins exist in Drosophila and C. elegans. Mutations in the human MCOLN1 gene cause mucolipodosis IV (MIM 262650) (Karacsonyi et al., 2007 [PubMed 17662026]).[supplied by OMIM, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-84937887-A-T is Benign according to our data. Variant chr1-84937887-A-T is described in ClinVar as [Benign]. Clinvar id is 711275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00796 (1213/152366) while in subpopulation AFR AF= 0.0273 (1137/41582). AF 95% confidence interval is 0.026. There are 15 homozygotes in gnomad4. There are 552 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCOLN2	NM_153259.4	c.1213-10T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370608.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCOLN2	ENST00000370608.8	c.1213-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_153259.4
MCOLN2	ENST00000531325.5	n.1454-10T>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
MCOLN2	ENST00000284027.5	c.1129-10T>A		splice_polypyrimidine_tract_variant, intron_variant		5		P1
MCOLN2	ENST00000463065.5	c.*147-10T>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 1209 AN: 152248 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00210 AC: 528 AN: 250998 Hom.: 6 AF XY: 0.00147 AC XY: 200 AN XY: 135660

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000787 AC: 1151 AN: 1461776 Hom.: 15 Cov.: 31 AF XY: 0.000650 AC XY: 473 AN XY: 727194

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00796 AC: 1213 AN: 152366 Hom.: 15 Cov.: 32 AF XY: 0.00741 AC XY: 552 AN XY: 74510

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00366 Hom.: 2

Bravo AF: 0.00884

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.0
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.18		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: rs139499028; hg19: chr1-85403570;