chr11-123097954-T-C

Variant names:

• chr11-123097954-T-C
• rs879253855
• NM_024769.5:c.29-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_024769.5(CLMP):​c.29-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000719 in 1,389,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CLMP NM_024769.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 2 publications found

Genes affected

CLMP (HGNC:24039): (CXADR like membrane protein) This gene encodes a type I transmembrane protein that is localized to junctional complexes between endothelial and epithelial cells and may have a role in cell-cell adhesion. Expression of this gene in white adipose tissue is implicated in adipocyte maturation and development of obesity. This gene is also essential for normal intestinal development and mutations in the gene are associated with congenital short bowel syndrome. [provided by RefSeq, Aug 2015]

CLMP Gene-Disease associations (from GenCC):

• congenital short bowel syndrome, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• congenital short bowel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288061 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14081997 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -15, new splice context is: ctctgcattactcattaaAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024769.5. 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
	CLMP	NM_024769.5	MANE Select	c.29-2A>G		splice_acceptor intron	N/A	NP_079045.1	Q9H6B4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLMP	ENST00000448775.4	TSL:1 MANE Select	c.29-2A>G		splice_acceptor intron	N/A	ENSP00000405577.2	Q9H6B4
	CLMP	ENST00000950922.1		c.42A>G	p.Pro14Pro	synonymous	Exon 2 of 7	ENSP00000620981.1
	CLMP	ENST00000715744.1		c.29-2A>G		splice_acceptor intron	N/A	ENSP00000520511.1	Q9H6B4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1389936 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685272

African (AFR) AF: 0.00 AC: 0 AN: 30584

American (AMR) AF: 0.00 AC: 0 AN: 33006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23236

East Asian (EAS) AF: 0.00 AC: 0 AN: 37566

South Asian (SAS) AF: 0.00 AC: 0 AN: 76770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074266

Other (OTH) AF: 0.00 AC: 0 AN: 56870

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Benign	0.97
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Benign	0.71	D
PhyloP100		5.5
GERP RS		5.0
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 34
DS_AL_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879253855; hg19: chr11-122968662;