rs56168869

chr22-24321542-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.34

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:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SPECC1L
• 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].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00744 (1134/152322) while in subpopulation AMR AF= 0.00849 (130/15310). AF 95% confidence interval is 0.00751. There are 10 homozygotes in gnomad4. There are 623 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPECC1L	NM_015330.6	c.562C>T	p.Leu188Phe	missense_variant	5/17	ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1	n.870C>T		non_coding_transcript_exon_variant	5/20
SPECC1L	NM_001145468.4	c.562C>T	p.Leu188Phe	missense_variant	4/16
SPECC1L	NM_001254732.3	c.562C>T	p.Leu188Phe	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14	c.562C>T	p.Leu188Phe	missense_variant	5/17	1	NM_015330.6	P1

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1134 AN: 152204 Hom.: 10 Cov.: 33

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

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

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

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SPECC1L: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Oculomaxillofacial dysostosis;CN306405:Teebi hypertelorism syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 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
MetaRNN	Benign	0.0059	T;T;T;T;T
MetaSVM	Uncertain	0.038	D
MutationTaster	Benign	1.0	D;D;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

Other links and lift over

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