22-24321542-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_015330.6(SPECC1L):​c.562C>T​(p.Leu188Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,614,182 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 10 hom., cov: 33)
Exomes 𝑓: 0.0064 ( 61 hom. )

Consequence

SPECC1L
NM_015330.6 missense

Scores

7
4
5

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.34
Variant links:
Genes affected
SPECC1L (HGNC:29022): (sperm antigen with calponin homology and coiled-coil domains 1 like) This gene encodes a coiled-coil domain containing protein. The encoded protein may play a critical role in actin-cytoskeletal reorganization during facial morphogenesis. Mutations in this gene are a cause of oblique facial clefting-1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A read-through transcript composed of SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and the downstream ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]
SPECC1L-ADORA2A (HGNC:49185): (SPECC1L-ADORA2A readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) genes on chromosome 22. The readthrough transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Jun 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0059348345).
BP6
Variant 22-24321542-C-T is Benign according to our data. Variant chr22-24321542-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-24321542-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 1134 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPECC1LNM_015330.6 linkc.562C>T p.Leu188Phe missense_variant Exon 5 of 17 ENST00000314328.14 NP_056145.5 Q69YQ0-1B2RMV2
SPECC1LNM_001145468.4 linkc.562C>T p.Leu188Phe missense_variant Exon 4 of 16 NP_001138940.4 B2RMV2
SPECC1LNM_001254732.3 linkc.562C>T p.Leu188Phe missense_variant Exon 4 of 15 NP_001241661.3 Q69YQ0-2
SPECC1L-ADORA2ANR_103546.1 linkn.870C>T non_coding_transcript_exon_variant Exon 5 of 20

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPECC1LENST00000314328.14 linkc.562C>T p.Leu188Phe missense_variant Exon 5 of 17 1 NM_015330.6 ENSP00000325785.8 Q69YQ0-1
SPECC1L-ADORA2AENST00000358654.2 linkn.562C>T non_coding_transcript_exon_variant Exon 5 of 20 2 ENSP00000351480.2 F8WAN1

Frequencies

GnomAD3 genomes
AF:
0.00745
AC:
1134
AN:
152204
Hom.:
10
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000941
Gnomad AMI
AF:
0.0318
Gnomad AMR
AF:
0.00850
Gnomad ASJ
AF:
0.00836
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.0308
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00807
Gnomad OTH
AF:
0.0115
GnomAD3 exomes
AF:
0.00767
AC:
1930
AN:
251468
Hom.:
17
AF XY:
0.00781
AC XY:
1061
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000861
Gnomad AMR exome
AF:
0.00408
Gnomad ASJ exome
AF:
0.0106
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00134
Gnomad FIN exome
AF:
0.0294
Gnomad NFE exome
AF:
0.00819
Gnomad OTH exome
AF:
0.00961
GnomAD4 exome
AF:
0.00644
AC:
9415
AN:
1461860
Hom.:
61
Cov.:
32
AF XY:
0.00642
AC XY:
4667
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000836
Gnomad4 AMR exome
AF:
0.00443
Gnomad4 ASJ exome
AF:
0.00884
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00143
Gnomad4 FIN exome
AF:
0.0265
Gnomad4 NFE exome
AF:
0.00626
Gnomad4 OTH exome
AF:
0.00619
GnomAD4 genome
AF:
0.00744
AC:
1134
AN:
152322
Hom.:
10
Cov.:
33
AF XY:
0.00836
AC XY:
623
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.000938
Gnomad4 AMR
AF:
0.00849
Gnomad4 ASJ
AF:
0.00836
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.0308
Gnomad4 NFE
AF:
0.00807
Gnomad4 OTH
AF:
0.0113
Alfa
AF:
0.0145
Hom.:
747
Bravo
AF:
0.00587
TwinsUK
AF:
0.00512
AC:
19
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00802
AC:
69
ExAC
AF:
0.00723
AC:
878
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00889
EpiControl
AF:
0.00830

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 03, 2025- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2024SPECC1L: BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 29, 2017- -
Oculomaxillofacial dysostosis;CN306405:Teebi hypertelorism syndrome 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 25, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Benign
-0.012
T
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
.;D;.;.;D
MetaRNN
Benign
0.0059
T;T;T;T;T
MetaSVM
Uncertain
0.038
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.0
N;N;N;N;D
REVEL
Benign
0.25
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Vest4
0.75
MVP
0.72
MPC
1.3
ClinPred
0.017
T
GERP RS
5.6
gMVP
0.43

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: rs56168869; hg19: chr22-24717510; COSMIC: COSV100063606; API