14-77320450-C-G

Variant names:

• chr14-77320450-C-G
• rs151103906
• NM_013382.7:c.232G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_013382.7(POMT2):​c.232G>C​(p.Glu78Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,546,362 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E78E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: POMT2 NM_013382.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 1.03
• Publications: 3 publications found

Genes affected

POMT2 (HGNC:19743): (protein O-mannosyltransferase 2) The protein encoded by this gene is an O-mannosyltransferase that requires interaction with the product of the POMT1 gene for enzymatic function. The encoded protein is found in the membrane of the endoplasmic reticulum. Defects in this gene are a cause of Walker-Warburg syndrome (WWS).[provided by RefSeq, Oct 2008]

POMT2 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• myopathy caused by variation in POMT2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• autosomal recessive limb-girdle muscular dystrophy type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016834259).
• BP6: Variant 14-77320450-C-G is Benign according to our data. Variant chr14-77320450-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95541.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000932 (142/152302) while in subpopulation NFE AF = 0.00157 (107/68024). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013382.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	NM_013382.7	MANE Select	c.232G>C	p.Glu78Gln	missense	Exon 1 of 21	NP_037514.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.232G>C	p.Glu78Gln	missense	Exon 1 of 21	ENSP00000261534.4	Q9UKY4-1
	POMT2	ENST00000556326.5	TSL:1	n.232G>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000450630.1	Q9UKY4-2
	POMT2	ENST00000682795.1		c.232G>C	p.Glu78Gln	missense	Exon 1 of 22	ENSP00000507574.1	A0A804HJN3

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000697 AC: 102 AN: 146262 AF XY: 0.000601

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.00120 AC: 1667 AN: 1394060 Hom.: 3 Cov.: 30 AF XY: 0.00108 AC XY: 745 AN XY: 687898

African (AFR) AF: 0.000158 AC: 5 AN: 31616

American (AMR) AF: 0.0000840 AC: 3 AN: 35732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35760

South Asian (SAS) AF: 0.0000378 AC: 3 AN: 79270

European-Finnish (FIN) AF: 0.00218 AC: 96 AN: 43978

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.00138 AC: 1488 AN: 1078876

Other (OTH) AF: 0.00123 AC: 71 AN: 57954

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74462

African (AFR) AF: 0.000337 AC: 14 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00157 AC: 107 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000978 Hom.: 0

Bravo AF: 0.000786

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000616 AC: 5

ExAC AF: 0.000337 AC: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2N (1)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2;C3150416:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2;C3150418:Autosomal recessive limb-girdle muscular dystrophy type 2N (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2;C3150416:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2;C3150418:Autosomal recessive limb-girdle muscular dystrophy type 2N;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)
-	-	1	not specified (1)
-	-	1	POMT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.15	N
PhyloP100		1.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.28	T
Sift4G	Benign	0.43	T
Polyphen		0.0070	B
Vest4		0.084
MVP		0.80
MPC		0.11
ClinPred		0.033	T
GERP RS		-0.12
PromoterAI		-0.053	Neutral
Varity_R		0.15
gMVP		0.66
Mutation Taster		=93/7	polymorphism

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: rs151103906; hg19: chr14-77786793;