8-2942602-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033225.6(CSMD1):c.10405C>G(p.Pro3469Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,567,484 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (40 hom.)
• Consequence: CSMD1 NM_033225.6 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.17

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=0.0034969747).
• BP6: Variant 8-2942602-G-C is Benign according to our data. Variant chr8-2942602-G-C is described in ClinVar as [Benign]. Clinvar id is 3045826.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000808 (123/152296) while in subpopulation SAS AF= 0.0243 (117/4824). AF 95% confidence interval is 0.0207. There are 5 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSMD1	NM_033225.6	c.10405C>G	p.Pro3469Ala	missense_variant, splice_region_variant	69/70	ENST00000635120.2
LOC105377785	NR_168443.1	n.1172-65966G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSMD1	ENST00000635120.2	c.10405C>G	p.Pro3469Ala	missense_variant, splice_region_variant	69/70	5	NM_033225.6	P4

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152178 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00313 AC: 575 AN: 183730 Hom.: 15 AF XY: 0.00407 AC XY: 400 AN XY: 98264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000798

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000751

Gnomad SAS exome AF: 0.0231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00135 AC: 1911 AN: 1415188 Hom.: 40 Cov.: 30 AF XY: 0.00196 AC XY: 1372 AN XY: 700220

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.000109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000736

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152296 Hom.: 5 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.00295 AC: 347

Asia WGS AF: 0.0120 AC: 41 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

Apr 20, 2021

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	0.066
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.4
Dann	Benign	0.095
DEOGEN2	Benign	0.010	T;.;.;.;T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	T;.;T;T;.;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	D;D;N;N
PrimateAI	Benign	0.33	T
REVEL	Benign	0.037
Sift4G	Benign	0.61	T;T;T;T;T;T
Polyphen		0.0020	.;.;.;.;B;B
Vest4		0.16, 0.19, 0.12, 0.12, 0.13
MutPred		0.24		.;.;.;.;Loss of disorder (P = 0.0756);Loss of disorder (P = 0.0756);
MVP		0.41
ClinPred		0.019	T
GERP RS		3.9
Varity_R		0.062
gMVP		0.19

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: rs375524577; hg19: chr8-2800124;