12-111034188-A-C

Variant names:

• chr12-111034188-A-C
• rs1031832941
• NM_015267.4:c.11A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015267.4(CUX2):​c.11A>C​(p.Asn4Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000801 in 1,248,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. N4S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: CUX2 NM_015267.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.77
• Publications: 0 publications found

Genes affected

CUX2 (HGNC:19347): (cut like homeobox 2) This gene encodes a protein which contains three CUT domains and a homeodomain; both domains are DNA-binding motifs. A similar gene, whose gene product possesses different DNA-binding activities, is located on chromosome on chromosome 7. Two pseudogenes of this gene have been identified on chromosomes 10 and 4. [provided by RefSeq, Jan 2013]

MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

MYL2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000309108 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19744098).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015267.4. 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
	CUX2	NM_015267.4	MANE Select	c.11A>C	p.Asn4Thr	missense	Exon 1 of 22	NP_056082.2	O14529

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUX2	ENST00000261726.11	TSL:1 MANE Select	c.11A>C	p.Asn4Thr	missense	Exon 1 of 22	ENSP00000261726.6	O14529
	CUX2	ENST00000933089.1		c.11A>C	p.Asn4Thr	missense	Exon 1 of 21	ENSP00000603148.1
	CUX2	ENST00000933091.1		c.11A>C	p.Asn4Thr	missense	Exon 1 of 21	ENSP00000603150.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.01e-7 AC: 1 AN: 1248610 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 620560

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25300

American (AMR) AF: 0.00 AC: 0 AN: 35772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17998

East Asian (EAS) AF: 0.00 AC: 0 AN: 19828

South Asian (SAS) AF: 0.00 AC: 0 AN: 81748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4662

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 978900

Other (OTH) AF: 0.00 AC: 0 AN: 46124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		6.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.052
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.023	D
Polyphen		0.60	P
Vest4		0.17
MutPred		0.23		Loss of catalytic residue at N4 (P = 0.145)
MVP		0.26
MPC		0.71
ClinPred		0.75	D
GERP RS		3.0
PromoterAI		0.12	Neutral
Varity_R		0.21
gMVP		0.12
Mutation Taster		=87/13	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: rs1031832941; hg19: chr12-111471992;