rs2235708

Variant names:

• chrX-139596585-G-A
• rs2235708
• NM_001171876.2:c.2469C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001171876.2(MCF2):​c.2469C>T​(p.Asp823Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,208,139 control chromosomes in the GnomAD database, including 499 homozygotes. There are 8,169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (116 hom., 1300 hem., cov: 23)
  • Exomes 𝑓: 0.019 (383 hom. 6869 hem.)
• Consequence: MCF2 NM_001171876.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153
• Publications: 2 publications found

Genes affected

MCF2 (HGNC:6940): (MCF.2 cell line derived transforming sequence) The oncogenic protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that exerts control over some members of the Rho family of small GTPases. Several transcript variants encoding different isoforms have been found for this gene. These isoforms exhibit different expression patterns and varying levels of GEF activity.[provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-139596585-G-A is Benign according to our data. Variant chrX-139596585-G-A is described in ClinVar as Benign. ClinVar VariationId is 1294008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171876.2. 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
	MCF2	NM_001171876.2	MANE Select	c.2469C>T	p.Asp823Asp	synonymous	Exon 23 of 29	NP_001165347.1	P10911-5
	MCF2	NM_001099855.2		c.2421C>T	p.Asp807Asp	synonymous	Exon 22 of 28	NP_001093325.1	P10911-3
	MCF2	NM_001171879.2		c.2289C>T	p.Asp763Asp	synonymous	Exon 20 of 26	NP_001165350.1	P10911-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCF2	ENST00000519895.6	TSL:2 MANE Select	c.2469C>T	p.Asp823Asp	synonymous	Exon 23 of 29	ENSP00000430276.1	P10911-5
	MCF2	ENST00000338585.6	TSL:1	c.2289C>T	p.Asp763Asp	synonymous	Exon 20 of 26	ENSP00000342204.6	P10911-4
	MCF2	ENST00000370576.9	TSL:1	c.2241C>T	p.Asp747Asp	synonymous	Exon 19 of 25	ENSP00000359608.4	P10911-1

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 4555 AN: 111641 Hom.: 116 Cov.: 23

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.0335

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0336 AC: 6151 AN: 182886 AF XY: 0.0298

Gnomad AFR exome AF: 0.0913

Gnomad AMR exome AF: 0.0615

Gnomad ASJ exome AF: 0.00401

Gnomad EAS exome AF: 0.0857

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0193 AC: 21211 AN: 1096445 Hom.: 383 Cov.: 30 AF XY: 0.0190 AC XY: 6869 AN XY: 362149

African (AFR) AF: 0.0904 AC: 2382 AN: 26354

American (AMR) AF: 0.0649 AC: 2280 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 97 AN: 19355

East Asian (EAS) AF: 0.116 AC: 3490 AN: 30170

South Asian (SAS) AF: 0.0309 AC: 1669 AN: 54091

European-Finnish (FIN) AF: 0.0220 AC: 892 AN: 40494

Middle Eastern (MID) AF: 0.0167 AC: 69 AN: 4126

European-Non Finnish (NFE) AF: 0.0110 AC: 9246 AN: 840723

Other (OTH) AF: 0.0236 AC: 1086 AN: 46026

GnomAD4 genome AF: 0.0408 AC: 4559 AN: 111694 Hom.: 116 Cov.: 23 AF XY: 0.0383 AC XY: 1300 AN XY: 33956

African (AFR) AF: 0.0874 AC: 2690 AN: 30764

American (AMR) AF: 0.0599 AC: 629 AN: 10509

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 16 AN: 2645

East Asian (EAS) AF: 0.0820 AC: 289 AN: 3526

South Asian (SAS) AF: 0.0271 AC: 73 AN: 2689

European-Finnish (FIN) AF: 0.0206 AC: 126 AN: 6112

Middle Eastern (MID) AF: 0.0275 AC: 6 AN: 218

European-Non Finnish (NFE) AF: 0.0126 AC: 670 AN: 53042

Other (OTH) AF: 0.0399 AC: 60 AN: 1502

Alfa AF: 0.0251 Hom.: 413

Bravo AF: 0.0474

EpiCase AF: 0.0122

EpiControl AF: 0.0106

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.18
DANN	Benign	0.88
PhyloP100		-0.15
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2235708; hg19: chrX-138678744; COSMIC: COSV58491739;