rs9358856

Positions:

• chr6-25426540-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017640.6(CARMIL1):​c.229G>A​(p.Val77Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,610,102 control chromosomes in the GnomAD database, including 17,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1522 hom., cov: 31)
  • Exomes 𝑓: 0.15 (16062 hom.)
• Consequence: CARMIL1 NM_017640.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281

Genes affected

CARMIL1 (HGNC:21581): (capping protein regulator and myosin 1 linker 1) Involved in several processes, including actin filament network formation; plasma membrane bounded cell projection organization; and positive regulation of cellular component organization. Located in several cellular components, including lamellipodium; macropinosome; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

CMAHP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004101813).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARMIL1	NM_017640.6	c.229G>A	p.Val77Ile	missense_variant	4/37	ENST00000329474.7	NP_060110.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARMIL1	ENST00000329474.7	c.229G>A	p.Val77Ile	missense_variant	4/37	1	NM_017640.6	ENSP00000331983.6

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20642 AN: 151170 Hom.: 1522 Cov.: 31

Gnomad AFR AF: 0.0854

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.162 AC: 40231 AN: 248160 Hom.: 3525 AF XY: 0.163 AC XY: 21893 AN XY: 134664

Gnomad AFR exome AF: 0.0855

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.145 AC: 212028 AN: 1458814 Hom.: 16062 Cov.: 31 AF XY: 0.146 AC XY: 105941 AN XY: 725690

Gnomad4 AFR exome AF: 0.0844

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.136 AC: 20636 AN: 151288 Hom.: 1522 Cov.: 31 AF XY: 0.141 AC XY: 10431 AN XY: 73836

Gnomad4 AFR AF: 0.0853

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.140

Gnomad4 OTH AF: 0.140

Alfa AF: 0.142 Hom.: 4167

Bravo AF: 0.132

TwinsUK AF: 0.132 AC: 489

ALSPAC AF: 0.130 AC: 500

ESP6500AA AF: 0.0770 AC: 299

ESP6500EA AF: 0.144 AC: 1196

ExAC AF: 0.160 AC: 19328

Asia WGS AF: 0.178 AC: 622 AN: 3476

EpiCase AF: 0.142

EpiControl AF: 0.138

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.011
DANN	Benign	0.83
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.020	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.018
Sift	Benign	0.23	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.25
ClinPred		0.0011	T
GERP RS		-1.4
Varity_R		0.026
gMVP		0.077

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: rs9358856; hg19: chr6-25426768; COSMIC: COSV61514777;