chr5-113043570-C-T

Variant names:

• chr5-113043570-C-T
• rs1445903770
• NM_001085377.2:c.2716G>A

Variant summary

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

The NM_001085377.2(MCC):​c.2716G>A​(p.Glu906Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.33
• Publications: 0 publications found

Genes affected

MCC (HGNC:6935): (MCC regulator of WNT signaling pathway) This gene is a candidate colorectal tumor suppressor gene that is thought to negatively regulate cell cycle progression. The orthologous gene in the mouse expresses a phosphoprotein associated with the plasma membrane and membrane organelles, and overexpression of the mouse protein inhibits entry into S phase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.13807943).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085377.2. 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
	MCC	NM_001085377.2	MANE Select	c.2716G>A	p.Glu906Lys	missense	Exon 17 of 19	NP_001078846.2	P23508-2
	MCC	NM_002387.3		c.2146G>A	p.Glu716Lys	missense	Exon 15 of 17	NP_002378.2	P23508-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCC	ENST00000408903.7	TSL:2 MANE Select	c.2716G>A	p.Glu906Lys	missense	Exon 17 of 19	ENSP00000386227.3	P23508-2
	MCC	ENST00000302475.9	TSL:1	c.2146G>A	p.Glu716Lys	missense	Exon 15 of 17	ENSP00000305617.4	P23508-1
	MCC	ENST00000515367.6	TSL:5	c.1957G>A	p.Glu653Lys	missense	Exon 15 of 17	ENSP00000421615.2	D6REY2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251252 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461804 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

⚠️ 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: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ 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.: 33

Alfa AF: 0.0000612 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		5.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.051
Sift	Uncertain	0.010	D
Sift4G	Benign	0.086	T
Polyphen		0.17	B
Vest4		0.38
MVP		0.27
MPC		0.095
ClinPred		0.22	T
GERP RS		5.3
Varity_R		0.17
gMVP		0.15
Mutation Taster		=80/20	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: rs1445903770; hg19: chr5-112379267;