rs2270374

Variant names:

• chr12-109591381-G-A
• rs2270374
• NM_000431.4:c.885+24G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000431.4(MVK):​c.885+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,601,586 control chromosomes in the GnomAD database, including 22,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1484 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21297 hom.)
• Consequence: MVK NM_000431.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.45
• Publications: 15 publications found

Genes affected

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MVK Gene-Disease associations (from GenCC):

• porokeratosis 3, disseminated superficial actinic type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hyperimmunoglobulinemia D with periodic fever

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mevalonic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• porokeratosis of Mibelli

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-109591381-G-A is Benign according to our data. Variant chr12-109591381-G-A is described in ClinVar as Benign. ClinVar VariationId is 439923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	NM_000431.4	MANE Select	c.885+24G>A		intron	N/A	NP_000422.1
	MVK	NM_001414512.1		c.960+24G>A		intron	N/A	NP_001401441.1
	MVK	NM_001114185.3		c.885+24G>A		intron	N/A	NP_001107657.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MVK	ENST00000228510.8	TSL:1 MANE Select	c.885+24G>A		intron	N/A	ENSP00000228510.3
	MVK	ENST00000546277.6	TSL:5	c.885+24G>A		intron	N/A	ENSP00000438153.2
	MVK	ENST00000636996.1	TSL:5	c.732+24G>A		intron	N/A	ENSP00000490869.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19106 AN: 152194 Hom.: 1488 Cov.: 33

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.149 AC: 37314 AN: 249608 AF XY: 0.152

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.168 AC: 243852 AN: 1449274 Hom.: 21297 Cov.: 30 AF XY: 0.167 AC XY: 120763 AN XY: 721800

African (AFR) AF: 0.0309 AC: 1025 AN: 33158

American (AMR) AF: 0.135 AC: 6040 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4955 AN: 26060

East Asian (EAS) AF: 0.160 AC: 6342 AN: 39614

South Asian (SAS) AF: 0.138 AC: 11880 AN: 86018

European-Finnish (FIN) AF: 0.108 AC: 5678 AN: 52666

Middle Eastern (MID) AF: 0.186 AC: 1066 AN: 5742

European-Non Finnish (NFE) AF: 0.179 AC: 197103 AN: 1101294

Other (OTH) AF: 0.163 AC: 9763 AN: 60036

GnomAD4 genome AF: 0.125 AC: 19104 AN: 152312 Hom.: 1484 Cov.: 33 AF XY: 0.122 AC XY: 9052 AN XY: 74476

African (AFR) AF: 0.0352 AC: 1463 AN: 41562

American (AMR) AF: 0.140 AC: 2137 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3470

East Asian (EAS) AF: 0.141 AC: 729 AN: 5180

South Asian (SAS) AF: 0.129 AC: 624 AN: 4828

European-Finnish (FIN) AF: 0.0987 AC: 1048 AN: 10620

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11883 AN: 68028

Other (OTH) AF: 0.146 AC: 309 AN: 2114

Alfa AF: 0.153 Hom.: 751

Bravo AF: 0.127

Asia WGS AF: 0.143 AC: 498 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0010
DANN	Benign	0.45
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2270374; hg19: chr12-110029186; COSMIC: COSV57332438; COSMIC: COSV57332438;