2-189877648-A-G

Variant names:

• chr2-189877648-A-G
• rs256552
• ENST00000772194.1:n.265+1762T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000772194.1(ENSG00000300477):​n.265+1762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 512,102 control chromosomes in the GnomAD database, including 18,205 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (11401 hom., cov: 32)
  • Exomes 𝑓: 0.16 (6804 hom.)
• Consequence: ENSG00000300477 ENST00000772194.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.860
• Publications: 8 publications found

Genes affected

ENSG00000300477 (HGNC:):

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000772194.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	NM_000534.5	MANE Select	c.*212A>G		downstream_gene	N/A	NP_000525.1
	PMS1	NM_001321045.2		c.*212A>G		downstream_gene	N/A	NP_001307974.1
	PMS1	NM_001321047.2		c.*212A>G		downstream_gene	N/A	NP_001307976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000300477	ENST00000772194.1		n.265+1762T>C		intron	N/A
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.*212A>G		downstream_gene	N/A	ENSP00000406490.3
	PMS1	ENST00000409593.5	TSL:1	c.*212A>G		downstream_gene	N/A	ENSP00000387169.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44837 AN: 152000 Hom.: 11374 Cov.: 32

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.159 AC: 57110 AN: 359986 Hom.: 6804 Cov.: 3 AF XY: 0.156 AC XY: 29179 AN XY: 187054

African (AFR) AF: 0.692 AC: 7716 AN: 11152

American (AMR) AF: 0.209 AC: 3311 AN: 15830

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 1309 AN: 11634

East Asian (EAS) AF: 0.257 AC: 6927 AN: 26966

South Asian (SAS) AF: 0.166 AC: 5433 AN: 32792

European-Finnish (FIN) AF: 0.171 AC: 3485 AN: 20426

Middle Eastern (MID) AF: 0.171 AC: 273 AN: 1600

European-Non Finnish (NFE) AF: 0.114 AC: 24796 AN: 217882

Other (OTH) AF: 0.178 AC: 3860 AN: 21704

GnomAD4 genome AF: 0.295 AC: 44907 AN: 152116 Hom.: 11401 Cov.: 32 AF XY: 0.293 AC XY: 21774 AN XY: 74372

African (AFR) AF: 0.693 AC: 28725 AN: 41456

American (AMR) AF: 0.220 AC: 3361 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.241 AC: 1248 AN: 5174

South Asian (SAS) AF: 0.173 AC: 831 AN: 4816

European-Finnish (FIN) AF: 0.183 AC: 1935 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7778 AN: 68020

Other (OTH) AF: 0.254 AC: 535 AN: 2108

Alfa AF: 0.280 Hom.: 2004

Bravo AF: 0.316

Asia WGS AF: 0.214 AC: 743 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.31
DANN	Benign	0.55
PhyloP100		-0.86
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs256552; hg19: chr2-190742374;