chr15-57438339-A-T

Variant names:

• chr15-57438339-A-T
• rs139876229
• NM_032866.5:c.340A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032866.5(CGNL1):​c.340A>T​(p.Ile114Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. I114V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CGNL1 NM_032866.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 4 publications found

Genes affected

CGNL1 (HGNC:25931): (cingulin like 1) This gene encodes a member of the cingulin family. The encoded protein localizes to both adherens and tight cell-cell junctions and mediates junction assembly and maintenance by regulating the activity of the small GTPases RhoA and Rac1. Heterozygous chromosomal rearrangements resulting in association of the promoter for this gene with the aromatase gene are a cause of aromatase excess syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023150444).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032866.5. 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
	CGNL1	NM_032866.5	MANE Select	c.340A>T	p.Ile114Leu	missense	Exon 2 of 19	NP_116255.2
	CGNL1	NM_001252335.2		c.340A>T	p.Ile114Leu	missense	Exon 3 of 20	NP_001239264.1	Q0VF96-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CGNL1	ENST00000281282.6	TSL:1 MANE Select	c.340A>T	p.Ile114Leu	missense	Exon 2 of 19	ENSP00000281282.5	Q0VF96-1
	CGNL1	ENST00000955758.1		c.340A>T	p.Ile114Leu	missense	Exon 2 of 20	ENSP00000625817.1
	CGNL1	ENST00000860577.1		c.340A>T	p.Ile114Leu	missense	Exon 2 of 19	ENSP00000530636.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.0010
DANN	Benign	0.47
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.41	N
PhyloP100		-1.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.093		Loss of glycosylation at S112 (P = 0.129)
MVP		0.12
MPC		0.018
ClinPred		0.032	T
GERP RS		-9.3
Varity_R		0.026
gMVP		0.31
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: rs139876229; hg19: chr15-57730537;