rs545661620

Positions:

• chr15-66489770-CTATT-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_006049.4(SNAPC5):​c.*965_*968delAATA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,610,934 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: SNAPC5 NM_006049.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:2 B:12
• Conservation: PhyloP100: -0.0830

Genes affected

MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

ENSG00000261351 (HGNC:):

SNAPC5 (HGNC:15484): (small nuclear RNA activating complex polypeptide 5) This gene encodes a subunit of the small nuclear RNA (snRNA)-activating protein complex that plays a role in the transcription of snRNA genes. This complex binds to the promoters of snRNA genes transcribed by either RNA polymerase II or III and recruits other regulatory factors to activate snRNA gene transcription. The encoded protein may play a role in stabilizing this complex. A pseudogene of this gene has been identified on chromosome 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 15-66489770-CTATT-C is Benign according to our data. Variant chr15-66489770-CTATT-C is described in ClinVar as [Benign]. Clinvar id is 44586.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-66489770-CTATT-C is described in Lovd as [Likely_benign]. Variant chr15-66489770-CTATT-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K1	NM_002755.4	c.1068+12_1068+15delTATT		intron_variant		ENST00000307102.10	NP_002746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K1	ENST00000307102.10	c.1068+12_1068+15delTATT		intron_variant		1	NM_002755.4	ENSP00000302486.5

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00223 AC: 560 AN: 251462 Hom.: 1 AF XY: 0.00223 AC XY: 303 AN XY: 135902

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00304 AC: 4427 AN: 1458606 Hom.: 7 AF XY: 0.00298 AC XY: 2162 AN XY: 725872

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74494

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00248

EpiCase AF: 0.00469

EpiControl AF: 0.00456

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2015	c.1068+12_1068+15delTATT in intron 10 of MAP2K1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0 .3% (214/66740) of European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2019	Variant summary: MAP2K1 c.1068+12_1068+15delTATT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 251462 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1440 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1068+12_1068+15delTATT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions including an expert panel, ClinGen, (evaluation after 2014) cite the variant three times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ENSG00000261351: BS2; MAP2K1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	- -

RASopathy Benign:3

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 09, 2017	The filtering allele frequency of the c.1068+12_1068+15delTATT variant in the MAP2K1 gene is 0.285% (214/66740) of European 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) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2012	The variant is found in NOONAN panel(s). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Noonan syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 22, 2020	- -

Cardio-facio-cutaneous syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516788; hg19: chr15-66782108;