8-2942574-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_033225.6(CSMD1):c.10433G>A(p.Ser3478Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,600,802 control chromosomes in the GnomAD database, including 1,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.056 (561 hom., cov: 32)
  • Exomes 𝑓: 0.020 (731 hom.)
• Consequence: CSMD1 NM_033225.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59

Genes affected

CSMD1 (HGNC:14026): (CUB and Sushi multiple domains 1) Predicted to act upstream of or within several processes, including learning or memory; mammary gland branching involved in pregnancy; and reproductive structure development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC105377785 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012851655).
• BP6: Variant 8-2942574-C-T is Benign according to our data. Variant chr8-2942574-C-T is described in ClinVar as [Benign]. Clinvar id is 3038258.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSMD1	NM_033225.6	c.10433G>A	p.Ser3478Asn	missense_variant	69/70	ENST00000635120.2
LOC105377785	NR_168443.1	n.1172-65994C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSMD1	ENST00000635120.2	c.10433G>A	p.Ser3478Asn	missense_variant	69/70	5	NM_033225.6	P4

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8523 AN: 152074 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0482

GnomAD3 exomes AF: 0.0265 AC: 5979 AN: 225504 Hom.: 240 AF XY: 0.0252 AC XY: 3060 AN XY: 121590

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.0155

Gnomad SAS exome AF: 0.0307

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0202 AC: 29248 AN: 1448610 Hom.: 731 Cov.: 30 AF XY: 0.0202 AC XY: 14520 AN XY: 719072

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.0306

Gnomad4 FIN exome AF: 0.00339

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0562 AC: 8556 AN: 152192 Hom.: 561 Cov.: 32 AF XY: 0.0545 AC XY: 4058 AN XY: 74450

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.0205

Gnomad4 SAS AF: 0.0265

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0477

Alfa AF: 0.0263 Hom.: 232

Bravo AF: 0.0621

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.151 AC: 559

ESP6500EA AF: 0.0179 AC: 146

ExAC AF: 0.0282 AC: 3396

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CSMD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.39
Dann	Benign	0.16
DEOGEN2	Benign	0.0027	T;.;.;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.094	T;.;T;T;.;T
MetaRNN	Benign	0.0013	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
REVEL	Benign	0.073
Sift4G	Benign	0.98	T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;B
Vest4		0.091, 0.10, 0.054, 0.030, 0.048
ClinPred		0.0012	T
GERP RS		0.56
Varity_R		0.040
gMVP		0.090

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: rs11984691; hg19: chr8-2800096; COSMIC: COSV59358308;