NM_001374258.1:c.2049A>G

Variant names:

• chr7-140749350-T-C
• rs9648696
• NM_001374258.1:c.2049A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA135110/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.30 (10970 hom., cov: 32)
  • Exomes 𝑓: 0.17 (26947 hom.)
• Consequence: BRAF NM_001374258.1 synonymous
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 1.58
• Publications: 32 publications found

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

BRAF Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. 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
	BRAF	NM_001374258.1	MANE Plus Clinical	c.2049A>G	p.Gly683Gly	synonymous	Exon 17 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.1929A>G	p.Gly643Gly	synonymous	Exon 16 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.2049A>G	p.Gly683Gly	synonymous	Exon 17 of 19	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.2049A>G	p.Gly683Gly	synonymous	Exon 17 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.1929A>G	p.Gly643Gly	synonymous	Exon 16 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2049A>G	p.Gly683Gly	synonymous	Exon 17 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45688 AN: 151904 Hom.: 10921 Cov.: 32

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.201 AC: 50505 AN: 250720 AF XY: 0.202

Gnomad AFR exome AF: 0.680

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.165 AC: 241653 AN: 1460534 Hom.: 26947 Cov.: 32 AF XY: 0.169 AC XY: 123032 AN XY: 726608

African (AFR) AF: 0.686 AC: 22935 AN: 33426

American (AMR) AF: 0.113 AC: 5058 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5514 AN: 26092

East Asian (EAS) AF: 0.156 AC: 6180 AN: 39580

South Asian (SAS) AF: 0.315 AC: 27154 AN: 86216

European-Finnish (FIN) AF: 0.143 AC: 7602 AN: 53338

Middle Eastern (MID) AF: 0.317 AC: 1740 AN: 5492

European-Non Finnish (NFE) AF: 0.138 AC: 153457 AN: 1111410

Other (OTH) AF: 0.199 AC: 12013 AN: 60306

GnomAD4 genome AF: 0.301 AC: 45786 AN: 152022 Hom.: 10970 Cov.: 32 AF XY: 0.299 AC XY: 22214 AN XY: 74346

African (AFR) AF: 0.669 AC: 27733 AN: 41434

American (AMR) AF: 0.183 AC: 2796 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 702 AN: 3464

East Asian (EAS) AF: 0.175 AC: 906 AN: 5168

South Asian (SAS) AF: 0.312 AC: 1505 AN: 4824

European-Finnish (FIN) AF: 0.152 AC: 1611 AN: 10592

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9760 AN: 67934

Other (OTH) AF: 0.276 AC: 582 AN: 2112

Alfa AF: 0.221 Hom.: 2667

Bravo AF: 0.316

Asia WGS AF: 0.279 AC: 972 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.162

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	RASopathy (4)
-	-	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 3 (1)
-	-	1	Noonan syndrome 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.9
DANN	Benign	0.74
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism (auto)

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: rs9648696; hg19: chr7-140449150; COSMIC: COSV56058907;