15-66489772-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_006049.4(SNAPC5):​c.*967T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,601,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

SNAPC5
NM_006049.4 3_prime_UTR

Scores

2

Clinical Significance

Likely benign reviewed by expert panel B:5

Conservation

PhyloP100: -0.321
Variant links:
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 15-66489772-A-G is Benign according to our data. Variant chr15-66489772-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 180895.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K1NM_002755.4 linkc.1068+9A>G intron_variant Intron 10 of 10 ENST00000307102.10 NP_002746.1 Q02750-1A4QPA9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K1ENST00000307102.10 linkc.1068+9A>G intron_variant Intron 10 of 10 1 NM_002755.4 ENSP00000302486.5 Q02750-1

Frequencies

GnomAD3 genomes
AF:
0.000231
AC:
35
AN:
151504
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000329
Gnomad ASJ
AF:
0.00379
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000133
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000310
AC:
78
AN:
251454
Hom.:
0
AF XY:
0.000228
AC XY:
31
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00446
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000185
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000225
AC:
326
AN:
1449698
Hom.:
1
Cov.:
29
AF XY:
0.000231
AC XY:
167
AN XY:
721540
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.000247
Gnomad4 ASJ exome
AF:
0.00465
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000143
Gnomad4 OTH exome
AF:
0.000517
GnomAD4 genome
AF:
0.000237
AC:
36
AN:
151622
Hom.:
0
Cov.:
32
AF XY:
0.000256
AC XY:
19
AN XY:
74182
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000329
Gnomad4 ASJ
AF:
0.00379
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000192
Hom.:
0
Bravo
AF:
0.000264

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

RASopathy Benign:2
Sep 24, 2019
ClinGen RASopathy Variant Curation Expert Panel
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.1068+9A>G intronic variant in the MAP2K1 gene is classified as likely benign because it does not alter an amino acid residue, is not located within the canonical splice site, and computational splice prediction tools do not predict an impact on splicing (BP4, BP7). It has been identified in 0.01123% (lower bound of the 95% CI of 8/35440) of Latino chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP4, BP7. -

Jan 12, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
May 27, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MAP2K1 c.1068+9A>G 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 0.00031 in 251454 control chromosomes (gnomAD). The observed variant frequency is approximately 124 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 benign. To our knowledge, no occurrence of c.1068+9A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

MAP2K1-related disorder Benign:1
Aug 17, 2020
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1
Aug 08, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
1.5
DANN
Benign
0.40
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368800650; hg19: chr15-66782110; API