2-63588667-A-C

Variant names:

• chr2-63588667-A-C
• rs2278718
• ENST00000485781.5:n.59A>C

Variant summary

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

The ENST00000485781.5(MDH1):​n.59A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 468,776 control chromosomes in the GnomAD database, including 11,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3713 hom., cov: 32)
  • Exomes 𝑓: 0.21 (8191 hom.)
• Consequence: MDH1 ENST00000485781.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0360
• Publications: 9 publications found

Genes affected

MDH1 (HGNC:6970): (malate dehydrogenase 1) This gene encodes an enzyme that catalyzes the NAD/NADH-dependent, reversible oxidation of malate to oxaloacetate in many metabolic pathways, including the citric acid cycle. Two main isozymes are known to exist in eukaryotic cells: one is found in the mitochondrial matrix and the other in the cytoplasm. This gene encodes the cytosolic isozyme, which plays a key role in the malate-aspartate shuttle that allows malate to pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes. Alternatively spliced transcript variants have been found for this gene. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Pseudogenes have been identified on chromosomes X and 6. [provided by RefSeq, Feb 2016]

WDPCP (HGNC:28027): (WD repeat containing planar cell polarity effector) This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WDPCP Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• heart defect - tongue hamartoma - polysyndactyly syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-63588667-A-C is Benign according to our data. Variant chr2-63588667-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 336779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000485781.5. 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
	WDPCP	NM_015910.7	MANE Select	c.-396T>G		upstream_gene	N/A	NP_056994.3
	WDPCP	NM_001354044.2		c.-720T>G		upstream_gene	N/A	NP_001340973.1
	WDPCP	NM_001354045.2		c.-396T>G		upstream_gene	N/A	NP_001340974.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	ENST00000485781.5	TSL:2	n.59A>C		non_coding_transcript_exon	Exon 1 of 4
	MDH1	ENST00000544381.4	TSL:2	c.-377A>C		5_prime_UTR	Exon 1 of 9	ENSP00000446395.2
	WDPCP	ENST00000431065.1	TSL:4	c.-396T>G		5_prime_UTR	Exon 1 of 4	ENSP00000396226.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29612 AN: 151792 Hom.: 3710 Cov.: 32

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.211 AC: 66813 AN: 316866 Hom.: 8191 Cov.: 0 AF XY: 0.204 AC XY: 34252 AN XY: 167708

African (AFR) AF: 0.0504 AC: 499 AN: 9894

American (AMR) AF: 0.215 AC: 3126 AN: 14558

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 1362 AN: 9828

East Asian (EAS) AF: 0.158 AC: 2958 AN: 18724

South Asian (SAS) AF: 0.126 AC: 5115 AN: 40720

European-Finnish (FIN) AF: 0.352 AC: 5913 AN: 16778

Middle Eastern (MID) AF: 0.0907 AC: 127 AN: 1400

European-Non Finnish (NFE) AF: 0.237 AC: 44186 AN: 186820

Other (OTH) AF: 0.194 AC: 3527 AN: 18144

GnomAD4 genome AF: 0.195 AC: 29625 AN: 151910 Hom.: 3713 Cov.: 32 AF XY: 0.199 AC XY: 14761 AN XY: 74222

African (AFR) AF: 0.0583 AC: 2417 AN: 41452

American (AMR) AF: 0.217 AC: 3308 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 446 AN: 3464

East Asian (EAS) AF: 0.182 AC: 935 AN: 5134

South Asian (SAS) AF: 0.125 AC: 602 AN: 4822

European-Finnish (FIN) AF: 0.384 AC: 4042 AN: 10528

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17286 AN: 67926

Other (OTH) AF: 0.172 AC: 362 AN: 2108

Alfa AF: 0.220 Hom.: 11950

Bravo AF: 0.177

Asia WGS AF: 0.122 AC: 426 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Bardet-Biedl syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.51
PhyloP100		-0.036
PromoterAI		0.048	Neutral
Mutation Taster		=300/0	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: rs2278718; hg19: chr2-63815801;