rs4540995

Variant names:

• chr14-77280469-T-C
• rs4540995
• NM_013382.7:c.1654-6A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-77280469-T-C
• chr14-77280469-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_013382.7(POMT2):​c.1654-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,614,048 control chromosomes in the GnomAD database, including 10,268 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1827 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8441 hom.)
• Consequence: POMT2 NM_013382.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001492
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.567
• Publications: 17 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-77280469-T-C is Benign according to our data. Variant chr14-77280469-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

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.1654-6A>G		splice_region intron	N/A	NP_037514.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMT2	ENST00000261534.9	TSL:1 MANE Select	c.1654-6A>G		splice_region intron	N/A	ENSP00000261534.4	Q9UKY4-1
	POMT2	ENST00000682795.1		c.1654-6A>G		splice_region intron	N/A	ENSP00000507574.1	A0A804HJN3
	POMT2	ENST00000923942.1		c.1654-6A>G		splice_region intron	N/A	ENSP00000594001.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21260 AN: 152088 Hom.: 1821 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.109 AC: 27303 AN: 251418 AF XY: 0.104

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.0614

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.100 AC: 146541 AN: 1461842 Hom.: 8441 Cov.: 38 AF XY: 0.0984 AC XY: 71594 AN XY: 727222

African (AFR) AF: 0.243 AC: 8120 AN: 33480

American (AMR) AF: 0.0638 AC: 2854 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 2546 AN: 26134

East Asian (EAS) AF: 0.230 AC: 9124 AN: 39700

South Asian (SAS) AF: 0.0520 AC: 4486 AN: 86256

European-Finnish (FIN) AF: 0.104 AC: 5577 AN: 53394

Middle Eastern (MID) AF: 0.0978 AC: 564 AN: 5768

European-Non Finnish (NFE) AF: 0.0962 AC: 106919 AN: 1111998

Other (OTH) AF: 0.105 AC: 6351 AN: 60388

GnomAD4 genome AF: 0.140 AC: 21288 AN: 152206 Hom.: 1827 Cov.: 32 AF XY: 0.138 AC XY: 10296 AN XY: 74410

African (AFR) AF: 0.232 AC: 9626 AN: 41512

American (AMR) AF: 0.0928 AC: 1419 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 316 AN: 3472

East Asian (EAS) AF: 0.214 AC: 1108 AN: 5170

South Asian (SAS) AF: 0.0559 AC: 270 AN: 4832

European-Finnish (FIN) AF: 0.108 AC: 1145 AN: 10604

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7047 AN: 68010

Other (OTH) AF: 0.123 AC: 261 AN: 2116

Alfa AF: 0.108 Hom.: 2147

Bravo AF: 0.144

Asia WGS AF: 0.110 AC: 385 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2N (2)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 (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 intellectual disability), type B2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.0
DANN	Benign	0.73
PhyloP100		0.57
PromoterAI		0.0014	Neutral
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.010		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: rs4540995; hg19: chr14-77746812; COSMIC: COSV55069509; COSMIC: COSV55069509;