rs2270421

Variant names:

• chr14-77320745-C-T
• rs2270421
• ENST00000556326.5:n.-64G>A

Variant summary

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

The ENST00000556326.5(POMT2):​n.-64G>A 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 0.284 in 1,562,322 control chromosomes in the GnomAD database, including 66,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5179 hom., cov: 32)
  • Exomes 𝑓: 0.29 (60946 hom.)
• Consequence: POMT2 ENST00000556326.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.694
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 14-77320745-C-T is Benign according to our data. Variant chr14-77320745-C-T is described in ClinVar as Benign. ClinVar VariationId is 314564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000556326.5. 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
	POMT2	NM_013382.7	MANE Select	c.-64G>A		5_prime_UTR	Exon 1 of 21	NP_037514.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000556326.5	TSL:1	n.-64G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000450630.1
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.-64G>A		5_prime_UTR	Exon 1 of 21	ENSP00000261534.4
	POMT2	ENST00000556326.5	TSL:1	n.-64G>A		5_prime_UTR	Exon 1 of 6	ENSP00000450630.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37466 AN: 151896 Hom.: 5174 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.222

GnomAD4 exome AF: 0.288 AC: 405477 AN: 1410318 Hom.: 60946 Cov.: 36 AF XY: 0.283 AC XY: 198344 AN XY: 700176

African (AFR) AF: 0.126 AC: 3971 AN: 31444

American (AMR) AF: 0.186 AC: 7237 AN: 38836

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5506 AN: 24160

East Asian (EAS) AF: 0.439 AC: 16965 AN: 38618

South Asian (SAS) AF: 0.137 AC: 11257 AN: 82128

European-Finnish (FIN) AF: 0.366 AC: 13466 AN: 36816

Middle Eastern (MID) AF: 0.168 AC: 673 AN: 4012

European-Non Finnish (NFE) AF: 0.302 AC: 330726 AN: 1096000

Other (OTH) AF: 0.269 AC: 15676 AN: 58304

GnomAD4 genome AF: 0.247 AC: 37477 AN: 152004 Hom.: 5179 Cov.: 32 AF XY: 0.246 AC XY: 18298 AN XY: 74320

African (AFR) AF: 0.137 AC: 5689 AN: 41532

American (AMR) AF: 0.199 AC: 3049 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3472

East Asian (EAS) AF: 0.414 AC: 2113 AN: 5102

South Asian (SAS) AF: 0.151 AC: 729 AN: 4828

European-Finnish (FIN) AF: 0.370 AC: 3912 AN: 10586

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.301 AC: 20397 AN: 67874

Other (OTH) AF: 0.224 AC: 473 AN: 2114

Alfa AF: 0.269 Hom.: 6329

Bravo AF: 0.232

Asia WGS AF: 0.251 AC: 869 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2N (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		0.69
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs2270421; hg19: chr14-77787088; COSMIC: COSV53623323; COSMIC: COSV53623323;