5-113028992-T-A

Position:

• chr5-113028992-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001085377.2(MCC):​c.2821A>T​(p.Ser941Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0112 in 1,614,020 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 31)
  • Exomes 𝑓: 0.011 (151 hom.)
• Consequence: MCC NM_001085377.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.64

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00965631).
• BP6: Variant 5-113028992-T-A is Benign according to our data. Variant chr5-113028992-T-A is described in ClinVar as [Benign]. Clinvar id is 771382.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0115 (16776/1461762) while in subpopulation AMR AF= 0.0271 (1212/44708). AF 95% confidence interval is 0.0258. There are 151 homozygotes in gnomad4_exome. There are 7945 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCC	NM_001085377.2	c.2821A>T	p.Ser941Cys	missense_variant	18/19	ENST00000408903.7	NP_001078846.2
MCC	NM_002387.3	c.2251A>T	p.Ser751Cys	missense_variant	16/17		NP_002378.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCC	ENST00000408903.7	c.2821A>T	p.Ser941Cys	missense_variant	18/19	2	NM_001085377.2	ENSP00000386227	P1
MCC	ENST00000302475.9	c.2251A>T	p.Ser751Cys	missense_variant	16/17	1		ENSP00000305617
MCC	ENST00000515367.6	c.2062A>T	p.Ser688Cys	missense_variant	16/17	5		ENSP00000421615

Frequencies

GnomAD3 genomes AF: 0.00808 AC: 1230 AN: 152140 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0102 AC: 2559 AN: 251250 Hom.: 37 AF XY: 0.00960 AC XY: 1303 AN XY: 135792

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00337

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.0115 AC: 16776 AN: 1461762 Hom.: 151 Cov.: 31 AF XY: 0.0109 AC XY: 7945 AN XY: 727180

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.0271

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.00867

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00808 AC: 1230 AN: 152258 Hom.: 9 Cov.: 31 AF XY: 0.00813 AC XY: 605 AN XY: 74444

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00962

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0104 Hom.: 7

Bravo AF: 0.00887

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00925 AC: 1123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.00967

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.97	D;D;D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.75
MPC		0.44
ClinPred		0.013	T
GERP RS		5.6
Varity_R		0.47
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs17313892; hg19: chr5-112364689;