15-90904337-C-T

Variant names:

• chr15-90904337-C-T
• rs776852590
• NM_006122.4:c.130C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006122.4(MAN2A2):​c.130C>T​(p.Arg44Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,978 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAN2A2 NM_006122.4 missense, splice_region
• Scores: Splicing: ADA: 0.6201
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51

Genes affected

MAN2A2 (HGNC:6825): (mannosidase alpha class 2A member 2) Predicted to enable alpha-mannosidase activity. Predicted to be involved in N-glycan processing and protein deglycosylation. Predicted to be integral component of membrane. Predicted to be active in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2A2	NM_006122.4	c.130C>T	p.Arg44Trp	missense_variant, splice_region_variant	Exon 2 of 23	ENST00000559717.6	NP_006113.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2A2	ENST00000559717.6	c.130C>T	p.Arg44Trp	missense_variant, splice_region_variant	Exon 2 of 23	2	NM_006122.4	ENSP00000452948.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250534 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460978 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.080	T;.;.;T;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	.;.;.;M;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D;D;D;.;D;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;D
Vest4		0.74, 0.74
MutPred		0.41		Loss of disorder (P = 0.0051);Loss of disorder (P = 0.0051);Loss of disorder (P = 0.0051);Loss of disorder (P = 0.0051);Loss of disorder (P = 0.0051);Loss of disorder (P = 0.0051);
MVP		0.89
MPC		0.93
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.31
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.020		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: rs776852590; hg19: chr15-91447567; COSMIC: COSV99069176; COSMIC: COSV99069176;